Medicine › Physiology

Adipose Tissue and Metabolism

Works Count: 120571

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Description

This cluster of papers focuses on the function and physiological significance of brown adipose tissue, including its role in thermogenesis, the involvement of PGC-1a and UCP1, mitochondrial dysfunction, insulin resistance, beige adipocytes, metabolic regulation, and the impact of exercise on brown adipose tissue. The papers also explore the molecular mechanisms underlying adaptive thermogenesis and the potential therapeutic implications for metabolic disorders.

Keywords

Brown Adipose Tissue; Thermogenesis; PGC-1a; Mitochondrial Dysfunction; Insulin Resistance; Beige Adipocytes; Metabolic Regulation; Exercise; UCP1; Adaptive Thermogenesis

The adipocyte-secreted protein Acrp30 enhances hepatic insulin action

2001-08-01

Anders H. Berg , Terry P. Combs , Xueliang Du +2 more

Cellular energy utilization and molecular origin of standard metabolic rate in mammals

1997-07-01

David F. S. Rolfe , Guy C. Brown

The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) … The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.

Metabolic control through the PGC-1 family of transcription coactivators

2005-06-01

Jiandie D. Lin , Christoph Handschin , Bruce M. Spiegelman

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Identification and Importance of Brown Adipose Tissue in Adult Humans

2009-04-08

Aaron M. Cypess , Sanaz Lehman , Gethin Williams +7 more

Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling … Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans.We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery.Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007).Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.

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Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ

2004-06-02

Frédéric Picard , Martin V. Kurtev , Namjin Chung +6 more

Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1

1999-07-01

Zhidan Wu , Pere Puigserver , Jan Andersson +7 more

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Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance

2003-05-15

Kitt Falk Petersen , Douglas E. Befroy , Sylvie Dufour +6 more

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants … Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1H nuclear magnetic resonance (NMR) spectroscopy, and with a approximately 40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13C/31P NMR spectroscopy. These data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.

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Dynamics of fat cell turnover in humans

2008-05-04

Kirsty L. Spalding , Peter Arner , Pål O. Westermark +7 more

Positional cloning of the mouse obese gene and its human homologue

1994-12-01

Yiying Zhang , Ricardo Proenca , Margherita Maffei +3 more

Cold-Activated Brown Adipose Tissue in Healthy Men

2009-04-08

Wouter D. van Marken Lichtenbelt , Joost W. Vanhommerig , Nanda M. Smulders +5 more

Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to … Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism.We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry.Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation.The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.

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A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis

1998-03-01

Pere Puigserver , Zhidan Wu , Cheol Won Park +3 more

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Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

2008-04-10

Adı́lson Guilherme , Joseph V. Virbasius , Vishwajeet Puri +1 more

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Recombinant Mouse OB Protein: Evidence for a Peripheral Signal Linking Adiposity and Central Neural Networks

1995-07-28

L. Arthur Campfield , Françoise J. Smith , Yves Guisez +2 more

The recent positional cloning of the mouse ob gene and its human homolog has provided the basis to investigate the potential role of the ob gene product in body weight … The recent positional cloning of the mouse ob gene and its human homolog has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob / ob and diet-induced obese mice but not in db / db obese mice. The behavioral effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and energy balance.

Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance

2008-01-01

Timothy R. Koves , John R. Ussher , Robert C. Noland +7 more

Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators

2006-10-01

Julie St‐Pierre , Stavit Drori , Marc Uldry +7 more

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Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes

2004-02-11

Kitt Falk Petersen , Sylvie Dufour , Douglas E. Befroy +2 more

Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.We performed hyperinsulinemic-euglycemic … Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.We performed hyperinsulinemic-euglycemic clamp studies in combination with infusions of [6,6-(2)H(2)]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton ((1)H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [(2)H(5)]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed (31)P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle.The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P<0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor alpha, interleukin-6, resistin, or adiponectin.These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.

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Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

2012-07-01

Jun Wu , Pontus Boström , Lauren M. Sparks +7 more

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Mechanisms linking obesity to insulin resistance and type 2 diabetes

2006-12-01

Steven E. Kahn , Rebecca L. Hull , Kristina M. Utzschneider

Functional Brown Adipose Tissue in Healthy Adults

2009-04-08

Kirsi A. Virtanen , Martin E. Lidell , Janne Orava +7 more

Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy … Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy specimens of this tissue from the first three consecutive subjects and documented messenger RNA (mRNA) and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.

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Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells

1992-10-01

Andrew Plump , Jonathan D. Smith , Tony Hayek +5 more

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1

2003-06-27

Mary‐Elizabeth Patti , Atul J. Butte , Sarah Crunkhorn +7 more

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic β cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated … Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic β cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican–American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 ( NRF-1 )-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPARγ coactivator 1-α and-β ( PGC1- α/ PPARGC1 and PGC1- β/ PERC ), coactivators of NRF-1 and PPAR γ-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

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Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres

2002-08-01

Jiandie D. Lin , Haiyan Wu , Paul T. Tarr +7 more

Development of a Strain of Spontaneously Hypertensive Rats

1963-01-01

Kôzô Okamoto , Kyuzo Aoki

A male rat with spontaneously high systolic blood pressures of 150 to 175 mmHg persisting for more than one month and a female rat with blood pressures slighty above the … A male rat with spontaneously high systolic blood pressures of 150 to 175 mmHg persisting for more than one month and a female rat with blood pressures slighty above the average, 130 to 140 mmHg, were selected from among 68 Wistar strain rats in normal condition and mated to obtain F1 rats. Of these F1 rats, males and females with hypertension (blood pressure exceeding 150 mmHg) persisting for more than a month (mostly over 2 months) were mated to produce F2 rats. The procedure was repeated to obtain F3, F4, F5 and F6 rats totaliag 380 animals. The weights and blood pressures (by the tail-water-plethysmographic method) were measured once weekly biginning at 4 weeks of age, and the results can be summarized as follows : 1. In body weight, the F rats showed little difference from the normal controls. 2. The blood pressures of F rats rose with age and from generation to generation, increasing significantly above those of normotensive controls of the same age after 20 weeks of age among female F1, after 15 weeks among male F1 and also male and female F2, and after 10 weeks among all F3 to F6 rats. E. g., the average systolic blood pressure of F5 at 25 weeks of age was 206+__-18.5 mmHg in the male and 193+__-20.5 mmHg in female rats. The blood pressures of normotensive controls remained at 131 to 136 mmHg in the male and 130 to 135 mmHg in female rats after 10 weeks of age. 3. Many F rats showed spontaneous hypertension. The incidence of the spontaneous occurrence of hypertension increased, and the development of hypertension occurred at younger ages from generation to generation. All of the F3 to F6, rats developed spontaneous hypertension within 15 weeks of age. Severe hypertension with blood pressures exceeding 200 mmHg began to observed among F2. The incidence of such severe hypertension increased with each generation, so that among male animals it inceased from only 9% in F2 to 35% in F3, 42% in F4, and 56% in F5, and in female animals from 3% in F2, 16% in F3, 33% in F4, and 37% in F5. The authors have named this Wistar strain of rats with spontaneous occurrence of hypertension as "spontaneously hypertensive rats (Okamoto-Aoki)". 4. The blood pressures of β-line rats from parents with very high blood pressures were significantly higher than among α-line rats from parents with moderately high blood pressures at the same age. 5. There was no difference in the blood pressures of offsprings resulting from inbreeding and those from cross breeding. The male blood pressure averaged about 10.6 mmHg above the female value in spontaneous hypertension, and hypertension developed at lower ages in the male. 6. It is a question for future study whether the spontaneous hypertension induced in rats in this Study is comparable in characteristics with essential hypertension in man.

Adipocyte differentiation from the inside out

2006-12-01

Evan D. Rosen , Ormond A. MacDougald

Mitochondrial Dysfunction and Type 2 Diabetes

2005-01-20

Bradford B. Lowell , Gerald I. Shulman

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in … Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.

Effects of the obese Gene Product on Body Weight Regulation in ob / ob Mice

1995-07-28

Mary Ann Pelleymounter , Mary Jane Cullen , Mary Baker +4 more

C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB … C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no changes in any of the metabolic parameters. These data suggest that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.

Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice

2001-02-06

Joachim Fruebis , Tsu‐Shuen Tsao , Sandrine Javorschi +5 more

Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe … Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe novel pharmacological properties of the protease-generated globular head domain of Acrp30 (gAcrp30). Acute treatment of mice with gAcrp30 significantly decreased the elevated levels of plasma free fatty acids caused either by administration of a high fat test meal or by i.v. injection of Intralipid. This effect of gAcrp30 was caused, at least in part, by an acute increase in fatty acid oxidation by muscle. As a result, daily administration of a very low dose of gAcrp30 to mice consuming a high-fat/sucrose diet caused profound and sustainable weight reduction without affecting food intake. Thus, gAcrp30 is a novel pharmacological compound that controls energy homeostasis and exerts its effect primarily at the peripheral level.

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AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α

2007-07-04

Sibylle Jäger , Christoph Handschin , Julie St‐Pierre +1 more

Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are … Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.

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A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

2012-01-01

Pontus Boström , Jun Wu , Mark P. Jedrychowski +7 more

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Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α (PGC-1α): Transcriptional Coactivator and Metabolic Regulator

2003-02-01

Pere Puigserver , Bruce M. Spiegelman

Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation … Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation is at the level of a transcriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1α. Once PGC-1α is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1α is achieved through specific interaction with a variety of transcription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1α therefore constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1α’s control of energy homeostasis suggests that it could be a target for antiobesity or diabetes drugs.

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Adipocytes as regulators of energy balance and glucose homeostasis

2006-12-13

Evan D. Rosen , Bruce M. Spiegelman

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AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity

1996-05-01

Erding Hu , Liang Peng , Bruce M. Spiegelman

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Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice

2009-04-14

Zhan‐Guo Gao , Jun Yin , Jin Zhang +5 more

OBJECTIVE We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat … OBJECTIVE We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet. RESEARCH DESIGN AND METHODS In dietary-obese C57BL/6J mice, sodium butyrate was administrated through diet supplementation at 5% wt/wt in the high-fat diet. Insulin sensitivity was examined with insulin tolerance testing and homeostasis model assessment for insulin resistance. Energy metabolism was monitored in a metabolic chamber. Mitochondrial function was investigated in brown adipocytes and skeletal muscle in the mice. RESULTS On the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice. Fasting blood glucose, fasting insulin, and insulin tolerance were all preserved in the treated mice. Body fat content was maintained at 10% without a reduction in food intake. Adaptive thermogenesis and fatty acid oxidation were enhanced. An increase in mitochondrial function and biogenesis was observed in skeletal muscle and brown fat. The type I fiber was enriched in skeletal muscle. Peroxisome proliferator–activated receptor-γ coactivator-1α expression was elevated at mRNA and protein levels. AMP kinase and p38 activities were elevated. In the obese mice, supplementation of butyrate led to an increase in insulin sensitivity and a reduction in adiposity. CONCLUSIONS Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse. The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.

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PRDM16 controls a brown fat/skeletal muscle switch

2008-08-01

Patrick Seale , Bryan C. Bjork , Wenli Yang +7 more

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Type 2 diabetes: principles of pathogenesis and therapy

2005-04-01

Michael Stümvoll , Barry J. Goldstein , Timon W. van Haeften

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Muscles, exercise and obesity: skeletal muscle as a secretory organ

2012-04-03

Bente Klarlund Pedersen , Mark A. Febbraio

Brown and beige fat: development, function and therapeutic potential

2013-09-29

Matthew Harms , Patrick Seale

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A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

2009-04-01

Christopher B. Newgard , Jie An , James R. Bain +7 more

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Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome

2000-12-01

B L Wajchenberg

Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution … Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.

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Brown Adipose Tissue: Function and Physiological Significance

2004-01-01

Barbara Cannon , Jan Nedergaard

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue is to transfer energy from food into … Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.

Metabolism of Isolated Fat Cells

1964-02-01

Martin Rodbell

Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes

2002-10-01

David E. Kelley , Jing He , Elizabeth V. Menshikova +1 more

Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of … Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O2 oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O2 oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O2 oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 ± 0.17, obese 0.76 ± 0.30, type 2 diabetes 0.56 ± 0.14 units/mU creatine kinase; P &lt; 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 ± 0.74, obese 3.24 ± 0.82, type 2 diabetes 2.48 ± 0.47 units/mU creatine kinase; P &lt; 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P &lt; 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.

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Relation of Body Fat Distribution to Metabolic Complications of Obesity*

1982-02-01

Ahmed H. Kissebah , N. Vydelingum , ROBERT MURRAY +3 more

The importance of body fat distribution as a predictor of metabolic aberrations was evaluated in 9 nonobese and 25 obese, apparently healthy women. Plasma glucose and insulin levels during oral … The importance of body fat distribution as a predictor of metabolic aberrations was evaluated in 9 nonobese and 25 obese, apparently healthy women. Plasma glucose and insulin levels during oral glucose loading were significantly higher in women with predominantly upper body segment obesity than in women with lower body segment obesity. Of the former group, 10 of 16 subjects had diabetic glucose tolerance results, while none of the latter group was diabetic. Fasting plasma triglyceride levels were also significantly higher in the upper body segment obese women. The site of adiposity in the upper body segment obese women was comprised of large fat cells, while in the lower body segment obese subjects, it was formed of normal size cells. In both types of obesity, abdominal fat cell size correlated significantly with postprandial plasma glucose and insulin levels. Thigh fat cell size gave no indication as to the presence of metabolic complications. Thigh adipocytes were also resistant to epinephrine-stimulated lipolysis, presumably due to an increase in a-adrenergic receptors. Thus, in women, the sites of fat predominance offer an important prognostic marker for glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. This association may be related to the disparate morphology and metabolic behavior of fat cells associated with different body fat distributions.

Macrophage-specific PPARγ controls alternative activation and improves insulin resistance

2007-05-21

Justin I. Odegaard , Roberto R. Ricardo-González , Matthew H. Goforth +7 more

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A STUDY OF THE ADRENOTROPIC RECEPTORS

1948-06-01

Raymond P. Ahlquist

Mechanisms of Insulin Action and Insulin Resistance

2018-08-01

Max C. Petersen , Gerald I. Shulman

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some … The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.

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IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN

1960-07-01

Rosalyn S. Yalow , Solomon A. Berson

For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations … For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations usually present in the circulation. Methods in use recently depend on the ability of insulin to exert an effect on the metabolism of glucose in vivo or in excised muscle or adipose tissue. Thus, the insulin concentration in plasma has been estimated: a) from the degree of hypoglycemia produced in hypophysectomized, adrenalectomized, alloxan-diabetic rats (1); b) from the augmentation of glucose uptake by isolated rat hemidiaphragm (2); or c) from the increased oxidation of glucose-1-C14 by the rat epididymal fat pad (3). Since there have been reports indicating the presence, in plasma, of inhibitors of insulin action (4) and of noninsulin substances capable of inducing an insulin-like effect (5,6), these procedures, while yielding interesting information regarding the effects of various plasmas on glucose metabolism in tissues, are of doubtful specificity for the measurement of insulin per se (5).

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Pathophysiology of Type 2 Diabetes Mellitus

2020-08-30

Unai Galicia-García , Asier Benito‐Vicente , Shifa Jebari +5 more

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability … Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

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Diverse Obesity Trajectories in a Family including Identical Twins with a Pathogenic MC4R Variant

2025-06-25

Joohyun Lim , Amanda J. Hooper , Joan Khoo +1 more | Obesity Facts

Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a … Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity, however weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusion: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.

Post-exercise ketone monoester administration concomitant with glucose stimulates glycogen repletion in soleus muscle in mice

2025-06-25

Yumiko Takahashi , Tatsuya Matsumoto , Wenxin Wang +3 more | AJP Cell Physiology

Although our group has demonstrated that the administration of β-hydroxybutyrate, a major type of ketone body, stimulated post-exercise glycogen repletion in isolated skeletal muscle, investigations of the effects of ketone … Although our group has demonstrated that the administration of β-hydroxybutyrate, a major type of ketone body, stimulated post-exercise glycogen repletion in isolated skeletal muscle, investigations of the effects of ketone supplementation on post-exercise muscle glycogen repletion in vivo have obtained conflicting results. Here, we investigated the effects of an oral intake of the ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) on post-exercise glycogen repletion in mouse skeletal muscles. Ten-week-old male Institute of Cancer Research mice ran on a treadmill at 25 m/min speed for 60 min. Immediately after the exercise, the mice were orally administered a solution containing 1.0 g/kg body weight (BW) of glucose and 2.0 g/kg BW of ketone monoester (KE solution) or a solution containing glucose and 1.11 g/kg BW of triolein for the adjustment of total calories to match the KE solution’s (Con solution). The KE-treated group showed significantly lower post-administration blood glucose concentrations and higher plasma insulin concentrations compared to those of the Con-treated group. The KE-treated group showed a 42.1% higher glycogen concentration in soleus muscle (slow-twitch fiber-dominant) at 60 min post-administration compared to that of Con group. There was no significant between-group difference in the glycogen concentration in the plantaris muscle (fast-twitch fiber-dominant). The KE-treated group’s soleus muscle also showed significantly lower phosphorylation levels of AMP-activated kinase Thr 172 at 30 min post-exercise compared to the level immediately post-exercise. These results demonstrated that a post-exercise administration of ketone monoester enhanced glycogen repletion, particularly in slow-twitch fiber-dominant muscle.

Correlation Between Irisin and Cognitive Functions in Alzheimer Dementia

2025-06-25

Patrizia Pignataro , Manuela Dicarlo , Chiara Zecca +7 more | Annals of Clinical and Translational Neurology

ABSTRACT Objective The myokine irisin, a recent positive mediator of exercise in the brain, shows neuroprotective functions against Alzheimer's disease (AD). The association between irisin and cognition has never been … ABSTRACT Objective The myokine irisin, a recent positive mediator of exercise in the brain, shows neuroprotective functions against Alzheimer's disease (AD). The association between irisin and cognition has never been explored in a biologically defined cohort of patients. Thus, in the present study, we investigated the association of irisin with multidomain cognition in patients showing dementia‐related symptomatology. Methods Cerebrospinal fluid (CSF) and serum irisin levels were evaluated using enzyme‐linked immunoassays in a cohort of subjects with a confirmed biomarker evidence of AD, including AD ( n = 82), mild cognitive impairment (MCI, n = 44), and subjective memory complaint (SMC, n = 20) patients. The results of this analysis were correlated with global cognitive efficiency assessed by Mini‐Mental State Examination, and multidomain cognition evaluated by a battery of psychometric tests. Results Decreased CSF and serum irisin levels were observed in AD and MCI patients compared to SMC. A significant correlation has been found between irisin in the CSF and global cognitive efficiency, as well as with specific cognitive domains such as memory, executive functions, attention, visuospatial abilities, and language. For serum irisin, the correlation analysis evidenced similar results to those observed for the CSF. Interpretation Our results highlight the key involvement of irisin in multidomain cognition, indicating its potential role as a cognitive biomarker of AD progression.

Adipose tissue dysfunction disrupts metabolic homeostasis: mechanisms linking fat dysregulation to disease

2025-06-24

Dana Bou Matar , Mahmoud Zhra , Walid Khaled Nassar +5 more | Frontiers in Endocrinology

Background Metabolic disease incidence continues rising globally. Adipose tissue dysfunction serves as a crucial pathophysiological mediator. We evaluate molecular mechanisms linking adipose dysfunction to metabolic dysregulation. Methods We systematically reviewed … Background Metabolic disease incidence continues rising globally. Adipose tissue dysfunction serves as a crucial pathophysiological mediator. We evaluate molecular mechanisms linking adipose dysfunction to metabolic dysregulation. Methods We systematically reviewed literature on adipose biology, stress mechanisms, inflammation, and metabolic networks. Analysis prioritized methodologically robust studies from the past decade. Results Adipose dysfunction disrupts metabolic homeostasis through complex molecular networks. Stressed adipocytes exhibit mitochondrial impairment and endoplasmic reticulum (ER) stress. These changes alter inflammatory mediators and adipokine secretion. Brown and beige adipose regulate energy balance via uncoupling protein 1 (UCP1)-mediated thermogenesis. Key transcriptional regulators, PGC-1α and PR domain containing 16 (PRDM16), control thermogenic adipocyte development. Cellular senescence contributes significantly to age-related adipose dysfunction through inflammatory secretory phenotypes. Brown fat also secretes specialized factors influencing whole-body metabolism, emphasizing adipose tissue’s endocrine function. Conclusion Adipose dysfunction represents a critical nexus in metabolic disease pathogenesis. Cellular stress, inflammation, and metabolic dysregulation converge at this point. Novel therapies targeting thermogenic activation and cellular senescence show promise. Despite advancing mechanistic understanding, developing effective interventions remains challenging due to adipose tissue’s complex roles in systemic metabolic regulation.

Impact of short-term housing temperature alteration on metabolic parameters and adipose tissue in female mice

2025-06-24

Henry A. Paz , C. G. Shashank , Lasya Buddha +7 more | Frontiers in Endocrinology

Introduction Ambient temperature significantly influences physiological and metabolic processes in rodents, affecting obesity and related disorders. Mice housed below thermoneutral temperatures exhibit increased energy expenditure and sympathetic-driven brown fat activation, … Introduction Ambient temperature significantly influences physiological and metabolic processes in rodents, affecting obesity and related disorders. Mice housed below thermoneutral temperatures exhibit increased energy expenditure and sympathetic-driven brown fat activation, whereas thermoneutral housing (~30°C) reduces these responses. This study aimed to determine whether short-term exposure to altered housing temperatures before and during pregnancy induces lasting changes in maternal adipose tissue. We hypothesized that even brief exposure during this critical window could cause persistent structural and molecular alterations in adipose tissue. Methods Female C57BL/6J mice were housed at cold (CE, 8°C), thermoneutral (TN, 30°C), or standard room temperature (RT, 22°C) conditions for one week before and throughout pregnancy. All mice were returned to RT post-delivery. Phenotypic assessments—including glucose tolerance, energy expenditure, histology, and proteomics—were performed after lactation. Results Temperature exposure did not significantly affect litter size or pup survival. CE-exposed mice showed increased total body weight driven by lean mass gains and reduced fat mass. Adipose tissue showed smaller adipocytes in iWAT and increased vascularity in BAT, though no persistent changes in thermogenic gene expression or glucose homeostasis were observed. Proteomic analysis of iWAT identified 38 differentially expressed proteins, with enrichment of pathways related to mitochondrial function and mTOR signaling. Discussion Short-term cold exposure induced lasting histological and proteomic changes in iWAT and BAT without sustained effects on energy metabolism, likely due to reversion to RT and limited sample size. Conclusion Brief temperature manipulation around pregnancy can durably alter maternal adipose tissue architecture and molecular signatures, underscoring ambient temperature as an important modulator of maternal metabolic adaptation.

Insulin resistance and exercise‐induced insulin sensitization in skeletal muscle: Insights from personalized phosphoproteomics

2025-06-24

Shun Masuda , Takashi Matsuzaka | Journal of Diabetes Investigation

Insulin resistance in muscle mainly disrupts non-canonical insulin signaling pathways. Exercise-induced MINDY1 S441 phosphorylation improves insulin sensitivity, highlighting its potential role in mediating exercise benefits in metabolic disease. Insulin resistance in muscle mainly disrupts non-canonical insulin signaling pathways. Exercise-induced MINDY1 S441 phosphorylation improves insulin sensitivity, highlighting its potential role in mediating exercise benefits in metabolic disease.

How the Mitochondrial Patch-Clamp Technique Establishes the ADP/ATP Carrier as a Major Uncoupling Protein in Non-adipose Tissues

2025-06-24

Ambre M. Bertholet , Matthew J. Milner | Oxford University Press eBooks

Abstract Mitochondrial heat production (also referred to as thermogenesis or uncoupling) is critical for the maintenance of core body temperature, protection against oxidative damage by reactive oxygen species, and the … Abstract Mitochondrial heat production (also referred to as thermogenesis or uncoupling) is critical for the maintenance of core body temperature, protection against oxidative damage by reactive oxygen species, and the reduction of fat deposits by increasing energy expenditure. The last has positioned thermogenic activation as one of the most promising therapeutic strategies for the treatment of metabolic disorders. Therefore, the uncoupling proteins (UCPs) that mediate this activation are of particular importance to the field of bioenergetics because they induce uncoupling through the transport of H+ across the inner mitochondrial membrane to release energy in the form of heat. While the UCP of the special thermogenic beige and brown adipose tissue, UCP1, has been characterized extensively, far less progress has been made in the identification of non-adipose UCPs. This has limited our mechanistic understanding of mitochondrial thermogenesis in most tissue types and has necessitated a methodology by which H+ transport could be measured in the native membrane environment and in isolation from other mitochondrial conductances. Here, we describe how the mitochondrial patch-clamp has established the ADP/ATP carrier as the UCP of non-adipose tissue and, in so doing, has redefined the mode of action of chemical uncouplers, controversial small molecules, offering the hope of safer and potent anti-obesogenic therapies.

Cysteine deficiency induces rapid weight loss via adipose tissue browning

2025-06-24

Olivia Tysoe | Nature Reviews Endocrinology

Exercise-Induced SOD3/H 2 O 2 Sulfenylates PKG1α to Restore Vasodilation in Diabetes

2025-06-24

Sudhahar Varadarajan , Kareem Abdelsaid , Philip Eaton +3 more | Circulation Research

The Effects of Omega-3 Supplementation Combined with Strength Training on Neuro-Biomarkers, Inflammatory and Antioxidant Responses, and the Lipid Profile in Physically Healthy Adults

2025-06-24

Sedat Okut , Murat Ozan , Yusuf Buzdağlı +5 more | Nutrients

Objectives: This study aimed to comprehensively investigate the physiological effects of omega-3 fatty acid supplementation combined with resistance training on the lipid profile, inflammatory and antioxidant responses, neuro-biomarkers, and physical … Objectives: This study aimed to comprehensively investigate the physiological effects of omega-3 fatty acid supplementation combined with resistance training on the lipid profile, inflammatory and antioxidant responses, neuro-biomarkers, and physical performance parameters in physically healthy young adults. Methods: Thirty physically active male participants were randomly assigned to an experimental group (omega-3 + resistance training) or a control group (resistance training only). Over eight weeks, both groups performed a standardized resistance training program three times per week. The experimental group additionally received 3150 mg/day of omega-3 fatty acids (EPA and DHA). Pre- and post-intervention assessments included blood biomarkers (LDL, HDL, triglycerides, IL-6, TNF-α, CRP, GSH, MDA, BDNF, serotonin, and dopamine) and physical performance tests (1RM, CMJ, RSI, 10 m sprint, and Illinois agility). Results: The experimental group showed significant improvements in the lipid profile, with decreases in LDL and triglyceride levels and an increase in HDL levels. Levels of the inflammatory cytokines IL-6 and TNF-α were significantly reduced, while GSH levels increased and MDA levels decreased, indicating an enhanced antioxidant status. The neuro-biomarker analysis revealed increased levels of BDNF, dopamine, and serotonin. Physical performance tests demonstrated greater improvements in muscular strength, power, speed, agility, and reaction-based performance in the omega-3 group compared to controls. Conclusions: These findings suggest that omega-3 supplementation, when combined with resistance training, has a multi-systemic enhancing effect on both physiological markers and physical performance. This combination may represent a promising strategy for optimizing athletic adaptations and recovery in physically active populations. Future studies should further explore these effects across different populations and training modalities.

Transcriptional regulation of porcine PABPN1 gene in adipogenesis

2025-06-24

Rongru Zhu , Xuelian Zhao , Minghang Chang +5 more | Animal Bioscience

This study was designed to reveal the transcriptional regulatory mechanism and effects of poly(A)-binding protein nuclear 1 (PABPN1)on adipogenesis and the polymorphisms as well. Transcription factors were identified with dual-luciferase … This study was designed to reveal the transcriptional regulatory mechanism and effects of poly(A)-binding protein nuclear 1 (PABPN1)on adipogenesis and the polymorphisms as well. Transcription factors were identified with dual-luciferase reporter assay, overexpression, site-directed mutagenesis, real-time quantitative PCR (qPCR), electrophoretic mobility shift assay and Chromatin immunoprecipitation-qPCR. Preadipocyte differentiation was measured with gain- and loss-of-function, Oil Red O staining and extraction assays. Single nucleotide polymorphisms (SNPs) were identified with direct sequencing of PCR products in the promoter, and the effects of SNPs on PABPN1 expression were identified with dual-luciferase reporter assay. Both CCAAT/enhancer-binding protein (C/EBP) α and β can regulate the expression of PABPN1 by directly binding to the promoter. PABPN1 promotes the preadipocyte differentiation in pigs. A total of three SNPs were identified, and the haplotype mutation, Haplotype GCC, significantly increases the promoter activity of PABPN1. PABPN1 promotes the preadipocyte differentiation as a downstream gene of C/EBP α and β. Haplotype GCC has the potential as a molecular marker for selecting fat trait in pigs.

Effects of the DUSP6 Gene on the Proliferation and Differentiation of Porcine Subcutaneous Preadipocytes

2025-06-24

Xiaosong Yang , Xuming Sun , Zhimin Du +7 more | Animal Bioscience

Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogen-activated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological … Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogen-activated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and quantitative real-time PCR were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARγ、C/EBPβ、FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs.

Redox Biology and Insulin-like Growth Factor-Binding Protein-6: A Potential Relationship

2025-06-23

Anna Rita Daniela Coda , Arcangelo Liso , Francesco Bellanti | Biology

Insulin-like growth factor-binding protein 6 (IGFBP-6) is primarily recognized for its inhibitory effects on insulin-like growth factor 2 (IGF-2), regulating processes such as cell proliferation, differentiation, and survival. However, recent … Insulin-like growth factor-binding protein 6 (IGFBP-6) is primarily recognized for its inhibitory effects on insulin-like growth factor 2 (IGF-2), regulating processes such as cell proliferation, differentiation, and survival. However, recent studies have revealed that IGFBP-6 also participates in a range of IGF-independent activities, notably in redox biology, immune regulation, and fibrosis. These IGF-independent actions involve interactions with redox-sensitive signaling pathways that influence mitochondrial metabolism, neutrophil function, and fibroblast activity, all of which are central to redox-dependent processes in inflammation and fibrosis. Despite these insights, the precise mechanisms by which IGFBP-6 modulates redox signaling remain largely unexplored. This review examines the growing understanding of IGFBP-6 beyond its classical role as an IGF-binding protein, with a focus on its involvement in redox homeostasis. By exploring these emerging roles, we aim to elucidate how IGFBP-6 contributes to redox homeostasis and to assess its potential as a therapeutic target in oxidative stress-related diseases, including fibrosis, cancer, and immune dysfunction.

High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging

2025-06-23

Patcharapong Pantiya , Chanisa Thonusin , Natticha Sumneang +7 more | Endocrinology and Metabolism

Adipose tissue ageing: implications for metabolic health and lifespan

2025-06-23

Guan Wang , Anying Song , Qiong Wang | Nature Reviews Endocrinology

The Long Noncoding RNA ΒFaar Promotes White Adipose Tissue Browning and Prevents Diet‐Induced Obesity

2025-06-23

Yue Yang , Bin Huang , Beverly E. Sha +7 more | Advanced Science

The conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) is a promising strategy for obesity treatment. It is previously identified βFaar as a conserved long noncoding RNA … The conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) is a promising strategy for obesity treatment. It is previously identified βFaar as a conserved long noncoding RNA (lncRNA) regulator of islet β-cell function in individuals with obesity, but its effect on WAT browning is not well understood. In this study, it is discovered that βFaar expression in adipose tissue markedly decreases with the progression of obesity in both mice and humans. βFaar in adipose tissue reduces lipid droplet (LD) size in WAT and promotes a browning phenotype in inguinal WAT (iWAT), leading to the amelioration of high-fat diet (HFD)-induced obesity. These effects can be attributed to crosstalk between βFaar and proteins within the master regulatory pathways of LD formation and WAT browning, including RAS oncogene family 18 (RAB18) and interferon regulatory factor 4 (IRF4). Specifically, βFaar inhibits LD swelling by binding to RAB18 and promoting IRF4 nuclear translocation, increases uncoupling protein 1 (UCP1) transcription, and further induces iWAT browning by binding to karyopherin subunit alpha 6 (KPNA6). Together, these results demonstrate the critical roles of βFaar in regulating iWAT browning and preserving metabolic health; thus, βFaar may be a potential therapeutic target for management of obesity and related disorders.

Lactobacillus regulate muscle fiber type conversion in Chinese native pigs via tryptophan metabolism

2025-06-23

Bo Song , Md. Abul Kalam Azad , Qian Zhu +4 more | npj Biofilms and Microbiomes

Identifying potential gut microbes and metabolites that can influence muscle fiber type is gaining interest in meat quality research. In this study, muscle fiber characteristics, muscle metabolite profiles, and gut … Identifying potential gut microbes and metabolites that can influence muscle fiber type is gaining interest in meat quality research. In this study, muscle fiber characteristics, muscle metabolite profiles, and gut microbiota and metabolome were compared among three pig breeds (Taoyuan black, TB; Xiangcun black, XB; and Duroc pigs). The results showed that the slow-twitch fiber percentage was higher (P < 0.05) in native pigs (TB and XB pigs) compared to Duroc pigs. The differences were mainly regulated by Lactobacillus abundance and tryptophan metabolism. Further, fecal microbiota transplantation from XB pigs transferred a higher slow-twitch fiber percentage, Lactobacillus abundance, kynurenic acid level, and AMPK/PGC-1α expression to mice. These findings suggest that Lactobacillus in the colon of TB and XB pigs, through kynurenic acid production, may promote slow-twitch fiber formation via the AMPK/PGC-1α signaling pathway.

Metabolic Stress‐Induced Choline Kinase α (CHKA) Activation in Endothelial Subpopulation Contributes to Diabetes‐Associated Microvascular Dysfunction

2025-06-23

Ling Ren , Linyu Zhang , Yun Bai +7 more | Advanced Science

Diabetes is a prevalent metabolic disorder, and its associated microvascular dysfunction plays a key role in the pathogenesis of complications such as retinopathy, nephropathy, and peripheral vascular disease. However, the … Diabetes is a prevalent metabolic disorder, and its associated microvascular dysfunction plays a key role in the pathogenesis of complications such as retinopathy, nephropathy, and peripheral vascular disease. However, the mechanism governing metabolic regulation and functional heterogeneity of endothelial dysfunction remains incompletely understood. This study investigates the role of metabolic stress-induced activation of choline kinase α (CHKA) in endothelial cell (EC) subpopulations, contributing to diabetes-induced microvascular dysfunction. Using single-cell RNA sequencing (scRNA-seq), three distinct EC subclusters are identified within retinal vessels. Among them, one subcluster characterized by elevated CHKA expression is associated with enhanced angiogenic activity. CHKA silencing in ECs inhibited angiogenic effects and reduced retinal vascular dysfunction in diabetic murine models. CHKA silencing also disrupted NAD+ metabolism, causing reduced NAD+ levels. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD+, partially reversed the anti-angiogenic effects induced by CHKA silencing. Mechanistically, CHKA regulated endothelial dysfunction through the NAD+-SIRT1-Notch signaling. Clinical sample analysis and Mendelian randomization studies provided strong evidence linking increased CHKA expression with diabetic microvascular complications. Collectively, this study advances the understanding of endothelial heterogeneity and identifies CHKA as a critical regulator of pathological angiogenesis, highlighting its potential as a therapeutic target for diabetic vascular complications.

Integrated Transcriptome and Metabolome Analysis of the Porcine Small Intestine During Weaning

2025-06-22

Jung Woong Yoon , Sangsu Shin , Tae Hyun Kim +1 more | Genes

Background/Objectives: Intestinal dysfunction during weaning in piglets causes declines in growth through hindered absorption capacity and intestinal barrier function, equating to economic losses for the porcine industry. Established strategies for … Background/Objectives: Intestinal dysfunction during weaning in piglets causes declines in growth through hindered absorption capacity and intestinal barrier function, equating to economic losses for the porcine industry. Established strategies for mitigating these negative issues are currently lacking. Methods: We evaluated biomolecular alterations induced by weaning stress through gene expression profiling and metabolome analysis using intestinal samples collected from piglets before weaning, 1 week after weaning, and 2 weeks after weaning. Results: We identified 701 differentially expressed genes related to weaning stress, representing the enrichment of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with immune response; inflammatory response; cell proliferation; cell adhesion; and carbohydrate, lipid, and calcium ion binding. In the metabolome analysis, ABC transporter; purine, pyrimidine, and Gly-Ser-Thr metabolisms; and the urea cycle were clustered as enriched KEGG pathways. Our results suggest that energy metabolism, including protein metabolism, is involved in the repair of the structural damage occurring in the intestine during weaning. Conclusions: This study highlights the importance of integrated analyses synthesizing molecular and metabolic mechanisms in elucidating complex biological responses and provides insights into markers that can be used to develop strategies for mitigating weaning stress in the porcine industry.

Relationship between oxygen radical absorbance capacity (ORAC) index, body composition and blood biochemical markers in overweight/obese compared to normal weight subjects: a cross-sectional study

2025-06-22

Zahra Madani , Maryam Moussavi Javardi , Golnaz Majdizadeh +4 more | Journal of Health Population and Nutrition

Obesity is an important preventable disease, which promotes the development of chronic disorders by altering several factors including oxidative stress. Dietary antioxidants protect the body against oxidative stress. The purpose … Obesity is an important preventable disease, which promotes the development of chronic disorders by altering several factors including oxidative stress. Dietary antioxidants protect the body against oxidative stress. The purpose of this study was to evaluate the potential association of oxygen radical absorbance capacity (ORAC) index with obesity and its associated features in adults. Participants were divided in two groups of normal weight and overweight/obesity. General characteristics were registered and a 147-item food frequency questionnaire was completed. Thereafter, anthropometric measurements were conducted. Biochemical indices were obtained from science and Research branch of Islamic Azad University of Tehran, Iran. The amount of the dietary ORAC index was estimated using the data provided by the USDA Foods Table. The results showed that there was a significant difference between the normal and overweight/obese groups in terms of body mass index (BMI) and waist-to-hip ratio (WHR) (P = 0.0001). Participants with normal weight consumed more fruits and vegetables than another group. Also, the dietary ORAC index in normal individuals was higher than the case group, but there was not significant difference (P = 0.352). There was also a significant inverse correlation between dietary ORAC and BMI and WHR, whereas a significant positive correlation between dietary ORAC and plasma HDL was observed (P < 0.05). Our findings suggest that dietary antioxidants is inversely associated with BMI, fasting blood glucose, triglyceride, total Cholesterol and LDL in both groups. It seems that following a diet rich in antioxidants can counteract obesity and its associated comorbidities.

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Association of the Gly482Ser polymorphism of the PGC-1α gene with aerobic performance and muscle strength

2025-06-21

Gabriel Rojas , Cristián Álvarez , Sandra C. Becerra +4 more | Retos

Introduction: The peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1α) gene has a polymorphism known as Gly482Ser that has been associated with aerobic capacity. Objective. To explore the association of the Gly482Ser … Introduction: The peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1α) gene has a polymorphism known as Gly482Ser that has been associated with aerobic capacity. Objective. To explore the association of the Gly482Ser polymorphism of the PGC-1α gene with aerobic performance and strength performance in young adults. Methods. The cross-sectional study cohort comprised 106 participants. The Gly482Ser polymorphism in PGC-1α was ascertained using the RFLP-PCR genotyping technique. Standardized physical evaluations were administered to assess aerobic capacity and muscular strength. Results. Participants who possess the homozygous Gly482 genotype demonstrated better physical performance assessed by the 6-minute walk test (6MWT), exhibited a reduced heart rate recovery time. Gly482 homozygous men achieved a greater walking distance. Women had a higher oxygen consumption during the Astrand test. No significant differences were observed in the Ruffier index. In terms of muscle strength evaluated through the push-up test, women with the Gly482 genotype were at a disadvantage, while this genotype did not affect hand grip and maximal isometric strength evaluations. For men, no statistically significant differences in muscle strength were observed measured by the hand grip test, the push-up test, or the maximum isometric strength. Discussion. The results are consistent with previous reports in which the Gly482 allele shows an association with aerobic performance, while the Ser482 allele has been associated with muscle strength and power. Conclusions. The findings indicate that the Gly482Ser polymorphism of the PGC-1α gene is correlated with variations in physical performance, with the Gly482 genotype demonstrating superior performance in aerobic capacity assessments among young adults.

IMPA2 Ameliorates High-Fat Diet-Induced Obesity by Enhancing Adaptive Thermogenesis in a Ca2+-activated Mitochondrial Biogenesis Pathway

2025-06-21

Min Chen , Li Lin , Yudan Zhou +6 more | Research Square (Research Square)

<title>Abstract</title> The identification of thermogenic adipocytes in humans proves that enhanced adaptive thermogenesis may help mitigate obesity. Although some evidence suggests a role for IMPA2 in cellular metabolism, its specific … <title>Abstract</title> The identification of thermogenic adipocytes in humans proves that enhanced adaptive thermogenesis may help mitigate obesity. Although some evidence suggests a role for IMPA2 in cellular metabolism, its specific impact on obesity and the underlying mechanisms remain underexplored. High-fat-diet (HFD)-induced obese mice were employed as experimental models. Cold exposure (4°C) or administration of the β3-adrenoceptor agonist CL316,243 was used to stimulate adipose thermogenesis. <italic>In vivo</italic> modulation of IMPA2 function was achieved through subcutaneous injection of adeno-associated virus (AAV). Body weight and energy metabolism were monitored, and browning was determined. The role and mechanisms of IMPA2 in thermogenesis were examined through adenovirus (Adv) treatment, followed by <italic>in vitro</italic> and <italic>in vivo</italic> analyses. Thermogenic stimulation increased IMPA2 level in murine inguinal white adipose tissue (iWAT), whereas obesity resulted in its downregulation. IMPA2 overexpression in iWAT accelerated WAT browning and thermogenesis, conferring protection against HFD-induced obesity and metabolic disturbances. Conversely, silencing IMPA2 reduced thermogenic gene levels in iWAT and inhibited WAT browning. Mechanistically, IMPA2 elevated myo-inositol (MI), inositol-1,4,5-trisphosphate (IP3) and intracellular calcium ion (Ca²⁺) levels, which subsequently activated Ca²⁺/calmodulin-dependent protein kinase IIα (CamKIIα) and PGC1α axis to increase mitochondrial biogenesis and thermogenic capacity in adipocytes. In conclusion, IMPA2 improves obesity and metabolic disorders, with its thermogenic enhancement mediated by the Ca²⁺-activated mitochondrial biogenesis pathway.

Histopathological Changes in Organs Due to High Environmental Heat in Male Wistar Rats

2025-06-21

Anjali Kumari , Rakesh Kumar Sinha | Indian Journal of Animal Research

Background: Environmental heat significantly affects the morphological and histological structures of mammals. This study aims to identify the histopathological changes induced by high environmental temperatures, specifically hyperthermia, in rats. Methods: … Background: Environmental heat significantly affects the morphological and histological structures of mammals. This study aims to identify the histopathological changes induced by high environmental temperatures, specifically hyperthermia, in rats. Methods: Twenty male wistar rats (n=20) were divided into two groups: (A) Experimental group (n=10), in which rats were exposed to hyperthermia in a biological oxygen demand (BOD) incubator until death and (B) Control group (n=10), kept at room temperature (24±1oC). Histopathological analysis was performed following standard procedures, including organ extraction, fixation, grossing, washing, dehydration, clearing, embedding, block preparation, section cutting, staining, mounting and microscopic examination. Result: Histopathological examination revealed that hyperthermia caused mild satellitosis and neuronophagia in the brain. The heart exhibited severely congested blood vessels with hemorrhages and cardiomyocytes showed pyknotic changes. In the kidneys, morphological changes included cloudy swelling of tubular epithelial cells with pyknotic alterations in the epithelial cell lining. The liver showed severe congestion in the sinusoid, hepatic artery and portal vein, along with rounding of Kupffer cells. The lungs exhibited hyperplasia of peri-bronchial lymphoid follicles.

Association between circulating irisin level and depression: a systematic review and meta-analysis

2025-06-20

Chengyan Han , Ziyang Zhou , Zhao Jianxing +2 more | Annals of Medicine

Previous studies have presented controversial results about the association between irisin and depression. This research is designed to explore the circulating irisin levels in depressive patients. From the earliest available … Previous studies have presented controversial results about the association between irisin and depression. This research is designed to explore the circulating irisin levels in depressive patients. From the earliest available records up to 18 July 2024, searches were conducted in databases of PubMed, Embase, Web of Science, the Cochrane Library, and Scopus, in order to identify the relevant articles assessing the correlation between irisin and depression in humans. Two reviewers screened reports, retrieved and collected data independently. Totally, eight articles with 2044 samples (733 depressive patients and 1311 non-depressive individuals) were involved. The results indicated lower circulating irisin levels in depression (standardized mean difference [SMD] = 0.60, 95% confidence interval [CI]: 0.08 to 1.12, p = 0.02). Subgroup analysis revealed decreased irisin levels in depressive Asian patients (SMD = 0.47, 95% CI: 0.05 to 0.90, p = 0.03), sample size greater than 100 participants (SMD = 1.20, 95% CI: 0.48 to 1.93, p = 0.001), ELISA kits not from Phoenix Pharmaceuticals (SMD = 0.47, 95% CI: 0.05 to 0.90, p = 0.03), blood sample of serum (SMD = 0.79, 95% CI: 0.18 to 1.40, p = 0.01), studies with two genders (SMD = 0.85, 95% CI: 0.26 to 1.43, p = 0.005). Moreover, six studies computed the correlation factor (r) values between irisin levels and depressive scores, and the combined findings indicated an inverse correlation for these two variables (r = -0.47, 95% CI: -0.69 to -0.24, p < 0.001). The results of this research demonstrated that irisin levels were decreased in depressive patients, and there was a negative correlation between irisin levels and depressive scores, indicating that the lower the circulating irisin level, the more severe the depressive symptoms.

Animal‐Free Setup of a 3D Mature Adipocyte‐Macrophage Co‐Culture to Induce Inflammation In Vitro

2025-06-20

Sophia Nowakowski , Svenja Nellinger , Franziska B. Albrecht +1 more | Advanced Healthcare Materials

Abstract Adipose tissue inflammation plays a central role in the pathogenesis of metabolic disorders. It is closely associated with immune cell infiltration, particularly macrophages, and the release of pro‐inflammatory cytokines. … Abstract Adipose tissue inflammation plays a central role in the pathogenesis of metabolic disorders. It is closely associated with immune cell infiltration, particularly macrophages, and the release of pro‐inflammatory cytokines. Reliable in vitro test systems that mimic the inflamed environment while being free of animal‐derived components are essential to explore new treatments for obesity‐related diseases. This study aims to develop a straightforward, animal‐free adipocyte‐macrophage co‐culture for investigating adipose tissue inflammation. Therefore, the human monocytic cell lines Mono Mac (MM6) and THP‐1 are co‐cultured with human primary mature adipocytes (ACs) encapsulated in gellan gum (GG) within a defined environment. Both monocytic cell lines are effectively activated by phorbol 12‐myristate 13‐acetate (PMA) and lipopolysaccharide (LPS) in the defined medium, exhibiting distinct cytokine profiles. A comparison between collagen and GG demonstrates that GG is a suitable animal‐free matrix material for ACs. PMA+LPS successfully activates the 3D adipocyte‐macrophage co‐culture to an inflammatory state for 72 h in the developed defined medium. Viability and intracellular lipid content remain high, and the functionality of ACs (perilipin A) in untreated models remains intact. This inflamed adipocyte‐macrophage co‐culture is easy to assemble and set up in a defined environment, making it a potential test system for anti‐inflammatory treatment strategies.

Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids

2025-06-19

Chul‐Hong Park , Minsung Park , M. Kelly +4 more | Cell Reports

Melatonin Alleviates MBP-Induced Oxidative Stress and Apoptosis in TM3 Cells via the SIRT1/PGC-1α Signaling Pathway

2025-06-19

Jingjing Liu , Qingsheng Guan , Shuang Li +2 more | International Journal of Molecular Sciences

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and … This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins.

Resonant recognition model-guided biophysical insights into POMC, leptin, adiponectin, BDNF, insulin, irisin, GDF-15 interactions & executing PBMT targeting leptin/BDNF circuit to attenuate obesity

2025-06-19

Tuhin Mukherjee , Ashok Pattnaik , Sitanshu Sekhar Sahu | Lasers in Medical Science

Cabergoline counteracts adipose and skeletal muscle lipid accumulation: A novel therapeutic approach to obesity?

2025-06-18

Mariarosaria Negri , Claudia Pivonello , Renata S. Auriemma +7 more | Biomedicine & Pharmacotherapy

Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress

2025-06-18

Rebecca Cornell , Ava Handley , Roger Pocock | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, … Abstract Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty. One-Sentence Summary Protecting mitochondria by integrating environmental signals

Irisin Mitigates Pro-inflammatory Cytokine Expression in Caco-2 Colon Cancer Cells: An In Vitro Study

2025-06-18

Ece Öztürk , EBUBEKIR BAKAN , Nurcan Kılıç Baygutalp +1 more | Research Square (Research Square)

<title>Abstract</title> Irisin is a myokine secreted by muscle tissue, recognized for its regulatory effects on inflammation. This study aimed to investigate the potential anti-inflammatory role of irisin in colon cancer … <title>Abstract</title> Irisin is a myokine secreted by muscle tissue, recognized for its regulatory effects on inflammation. This study aimed to investigate the potential anti-inflammatory role of irisin in colon cancer by evaluating its effects on the Caco-2 cell line. Specifically, we assessed pro-inflammatory cytokine levels (IL-6 and TNF-α), apoptotic marker Caspase-3 activity, and changes in the NF-κB signaling pathway using ELISA assays. Our results demonstrated a significant increase in IL-6 levels in the 100 nM irisin-treated group compared to controls (p < 0.05), and Caspase-3 activity significantly differed between the 10 nM and 100 nM irisin groups (p < 0.05). While direct antiproliferative effects of irisin on Caco-2 cells were not evident in cytotoxicity analyses, a significant increase in Caspase-3 activity suggested activation of apoptotic pathways. Additionally, the upregulation of NF-κB signaling—typically associated with cancer progression through inhibition of apoptosis—was observed following irisin treatment. In conclusion, these findings suggest that irisin modulates inflammatory and apoptotic responses in colon cancer cells, rather than exerting direct cytotoxic effects. Irisin's regulatory influence on the tumor microenvironment may offer potential therapeutic benefits in oncology. Further preclinical and clinical investigations are warranted to fully elucidate irisin’s role in cancer treatment.

Medial prefrontal cortex inputs to the dorsomedial striatum regulate motivation for wheel running in male mice

2025-06-17

Kazuhei Niitani , Ryoma Nishida , Y Ogura +3 more | Journal of Pharmacological Sciences

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

2025-06-17

Karina Cal , Alejandro Leyva , Jorge Rodriguez‐Duarte +7 more | Nature Metabolism

The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons

2025-06-17

Yuanxin Chen , Lianteng Zhi , S. Cui +3 more | bioRxiv (Cold Spring Harbor Laboratory)

Mitochondrial dysfunction and oxidative stress are central to Parkinson′ disease (PD) pathogenesis, particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in … Mitochondrial dysfunction and oxidative stress are central to Parkinson′ disease (PD) pathogenesis, particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons. Using a BAC transgenic mouse model overexpressing human LRRK2-R1441G, we crossed these mice with TH-mito-roGFP mice, enabling mitochondria-targeted redox imaging in DA neurons. The two-photon imaging of acute brain slices from 3-, 6-, and 10-month-old mice revealed a progressive elevated oxidative stress in SNc DA neurons and their striatal projections, accompanied with reduced respiratory complex activity and decline in mitochondrial health. Spatial transcriptomics via GeoMx Digital Spatial Profiler identified molecular changes linked to dysregulated mitochondrial uncoupling protein function and calcium homeostasis. These findings demonstrate age-dependent mitochondrial dysfunction in LRRK2-mutant SNc DA neurons, highlighting calcium channels and uncoupling proteins as potential therapeutic targets to slow PD progression.

A bioenergetic basis for multiorgan dysfunction in sepsis

2025-06-17

Elisa Jentho , Temitope W. Ademolue , Hessel Peters‐Sengers +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection 1 . With an estimated 49 million cases per year and ∼11 million related deaths … Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection 1 . With an estimated 49 million cases per year and ∼11 million related deaths 2 , sepsis is a global WHO health priority 3 . Failure to overcome sepsis morbidity and lethality 4,5 calls for alternative therapeutic approaches 6–8 . Here we report that adipocyte lipolysis is vital to prevent the pathogenesis of sepsis in mice. This protective response is evolutionary conserved, producing a plasma lipidomic profile 9,10 that reflects on the severity of clinical sepsis. Mechanistically, adipocyte lipolysis fuels energy metabolism to sustain adaptive thermoregulation to infection, via insulin production and insulin receptor (INSR) signaling in adipocytes. This metabolic-based defense strategy does not impact on bacterial burden, establishing disease tolerance to infection 11–14 . In conclusion, adipocyte lipolysis induces insulin to rewire energy metabolism and support organ function in response to infection.

Metabolic resilience rules sex-specific pain recovery during hormonal aging: a multi-omics analysis of neuropathy in mice.

2025-06-17

Sara Marinelli , Cláudia Rossi , Luisa Pieroni +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience, the ability to flexibly switch fuel sources … Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience, the ability to flexibly switch fuel sources and maintain energy homeostasis, rules successful recovery from nerve injury in a sex-dependent manner during aging. In 12-month-old male and female mice, corresponding to the perimenopausal phase in females and the onset of hormonal decline in both sexes, we induced sciatic nerve chronic constriction injury and performed multi-omics profiling during Wallerian degeneration, a phase known to trigger long-term neurobiological remodeling. Aging females exhibited early activation of fatty acid oxidation, increased resting energy expenditure, upregulation of mitochondrial redox enzymes and circulating progesterone and corticosterone. Proteomic and metabolomic analysis revealed pentose phosphate pathway enrichment and gluconeogenesis, supporting redox balance and metabolic flexibility. Conversely, males displayed persistent glycolytic reliance, long-chain acylcarnitine accumulation, suppression of adiponectin and PPARgamma, indicating metabolic inflexibility. Longitudinal behavioral analysis revealed that aging females recovered earlier and more fully than aging males, reversing the pattern previously shown in our adult mouse study, where females developed persistent pain and males recovered rapidly. These patterns highlight a non-linear, sex-specific interaction between biological aging and injury response, where hormonal decline reprograms the metabolic trajectory and reshapes pain outcomes. Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. These results define mechanistically anchored, sex- and age-specific biomarkers, and propose preclinical targets for timely, personalized interventions in age-associated neuropathic pain.

The role of adipose tissue in puberty and reproductive health

2025-06-17

Xin Ning , Qing Huang , Dou-Dou Guo +3 more | Frontiers in Endocrinology

Adipose tissue is an endocrine organ that signals energy status to the hypothalamic–pituitary–gonadal axis to regulate reproductive function. Notably, in mammals, adipose tissue biology—adipose tissue expansion and body fat distribution—is … Adipose tissue is an endocrine organ that signals energy status to the hypothalamic–pituitary–gonadal axis to regulate reproductive function. Notably, in mammals, adipose tissue biology—adipose tissue expansion and body fat distribution—is closely linked to the onset of puberty. Some studies showed that early adipose tissue development continues into childhood or adulthood, indicating its potential impact on reproductive function. Factors such as maternal obesity, childhood body mass index gain, and adolescent obesity significantly contribute to early puberty onset and negative reproductive events including menstrual irregularity, polycystic ovary syndrome, and male infertility. However, the connection between adipose tissue development before adulthood (prenatal stage and childhood) and reproductive function has not yet been fully investigated and reviewed. In this study, we present a comprehensive review of hormonal and inherent dimorphisms on adipose tissue development; there is a novel discussion about the link between adipose tissue expansion tracking throughout early life stages and reproductive disorders. Our study aims to elucidate how adipocyte development during critical periods of life can affect future reproductive health from sexual maturation to fertility and points to the clinical significance of further unlocking the underlying mechanism and weight management. As such, early prevention and long-term management for weight control might be considered as effective measures to mitigate obesity-induced reproductive comorbidities.

Enhanced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from young children with overweight/obesity and insulin resistance.

2025-06-17

Eugénia Carvalho , Reid D. Landes , Matthew Cotter +3 more | PubMed

Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found … Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole-body metabolism and/or biomarkers of metabolic health and inflammation. We stratified prepubertal children (ages 5-10 years) into three groups: normal weight insulin sensitive (N-IS; n = 20), overweight/obese insulin sensitive (O-IS; n = 28) and overweight/obese insulin resistant (O-IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole-body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D2O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole-body metabolism and biomarkers. O-IS and O-IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N-IS. Bioenergetics shifted towards glycolysis in O-IS PBMCs as compared to both N-IS and O-IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O-IR compared to O-IS children. PBMC respiration positively correlated with BMIz, HOMA-IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O-IS compared to N-IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration. PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole-body metabolism.

Ketone body driven lipid remodeling supports thermogenic adaptation to fasting

2025-06-17

Zahra Moazzami , Eric D. Queathem , Jiawen Ma +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Metabolic adaptation to fasting may have conferred survival advantage to early humans and predicts weight gain caused by overnutrition in modern societies. Fasting suppresses brown adipose tissue (BAT) thermogenesis; however, … Metabolic adaptation to fasting may have conferred survival advantage to early humans and predicts weight gain caused by overnutrition in modern societies. Fasting suppresses brown adipose tissue (BAT) thermogenesis; however, it is unclear how BAT rewires cellular metabolism to balance between energy conservation and heat generation. Here, we report that BAT in mice under fasting and cold challenge consumed ketone bodies, specifically acetoacetate (AcAc). Ablating liver ketogenesis decreased, while enhancing hepatic AcAc output defended, body temperature in mice facing the dual challenge. Using stable isotope tracing in brown adipocytes in vitro combined with quantitative analysis of metabolic fluxes and lipidomics in BAT from genetic mouse models, we disentangled the two metabolic fates of AcAc - terminal oxidation in the mitochondria and lipid biosynthesis in the cytosol. Notably, AcAc-sourced carbon preferentially supported polyunsaturated fatty acid synthesis in BAT, linking to the positive impact of intermittent fasting on lipid profiles in both mice and humans. Therefore, ketone body utilization by thermogenic adipocytes contributes to metabolic resilience of mammals and can be targeted to optimize benefits of dietary regimens.

β₂AR Agonists Sustain Thermogenesis and Leanness viaSympathofacilitation

2025-06-17

Samson W. Cheung , David Sidarta-Oliveira , Lu Yao +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Summary Human thermogenesis depends on β2-adrenoceptors (β2AR) expressed in thermogenic adipocytes, which are activated by norepinephrine released from sympathetic neurons. Whether β2AR also modulates thermogenesis via direct presynaptic action within … Summary Human thermogenesis depends on β2-adrenoceptors (β2AR) expressed in thermogenic adipocytes, which are activated by norepinephrine released from sympathetic neurons. Whether β2AR also modulates thermogenesis via direct presynaptic action within sympathetic neurons has remained unclear. Here, we identify Adrb2 expression in human and rodent cervical sympathetic neurons. β2AR agonism exerts neurotrophic effects and facilitates cholinergic responsiveness in mouse sympathetic neurons, indicating a sympathofacilitatory role. Selective deletion of β2AR in sympathetic neurons leads to impaired nerve activity in brown adipose tissue, sympathetic neuropathy, worsened fasting-induced hypothermia, and progressive obesity in chow-fed mice—without changes in food intake. These findings uncover a presynaptic role for β2AR in sustaining thermogenesis and regulating adiposity, suggesting sympathofacilitation as a therapeutic avenue for obesity. Highlights Human and mouse cervical sympathetic neurons express adrenoceptor beta 2 ( Adrb2 ) β2-adrenoceptor (β2AR) activation is neurotrophic and facilitates sympathetic neuronal excitability Loss of β2AR in sympathetic neurons leads to neuropathy in brown adipose tissue and reduced sympathetic activity Deletion of β2AR in sympathetic neurons exacerbates fasting-induced hypothermia and promotes obesity independently of food intake

GLP-1R agonist alleviate obesity and NAFLD by upregulates OTR to activating MAPK/ERK signalling pathway in liver through the brain–liver axis

2025-06-17

Weiping Jia , Xueying Li , Songtao Qi | Materials Technology

Associations between brown adipose tissue activity, serum lipid profiles, and cardiovascular events: insights from 18F-fluorodeoxyglucose PET/computed tomography analysis

2025-06-17

Kewei Yang , Ruiqiu Zhang , Xiaohui Zhang +7 more | Nuclear Medicine Communications

Objective This study investigated the associations between brown adipose tissue (BAT) metabolic parameters, serum lipid profiles, and cardiovascular disease (CVD) events. Methods A retrospective cohort study involving 13 530 patients … Objective This study investigated the associations between brown adipose tissue (BAT) metabolic parameters, serum lipid profiles, and cardiovascular disease (CVD) events. Methods A retrospective cohort study involving 13 530 patients who underwent 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/computed tomography between November 2019 and March 2024 was conducted to evaluate semiquantitative BAT indices, including the maximum standardized uptake value (B-SUV max ), total metabolic volume (TBMV), and total BAT glycolytic activity (TBG), as well as their associations to lipid profiles [total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and TC/HDL-C and LDL-C/HDL-C ratios) and CVD outcomes. Propensity score matching was applied, resulting in a comparison group of 74 BAT-positive patients and 148 BAT-negative controls. Results BAT-positive individuals exhibited significantly higher HDL-C levels ( P = 0.005) and lower TC/HDL-C ( P = 0.006) and LDL-C/HDL-C ( P = 0.014) ratios compared with controls, while no significant differences were observed in triglyceride, TC, or LDL-C levels. TBG showed the strongest correlations with HDL-C ( r = 0.256, P < 0.001), TC/HDL-C ( r = −0.223, P < 0.001), and LDL-C/HDL-C ( r = −0.195, P = 0.004), outperforming B-SUV max and TBMV. Patients exhibiting BAT had a lower incidence of CVD events compared to those without detectable BAT ( P = 0.018). Multivariate logistic regression analysis showed that the presence of BAT is an independent predictor of CVD events. Conclusion TBG is a moderate biomarker reflecting HDL-C levels and the ratios of TC/HDL-C and LDL-C/HDL-C, while detectable BAT activity independently correlates with reduced CVD risk, highlighting its potential for cardiovascular risk stratification.

Diesel exhaust particles attenuate skeletal muscle cell proliferation and induce skeletal muscle atrophy through activation of AMP-activated protein kinase

2025-06-17

Youngnam Kang , Hyun Joung Lim , Eunsook Park +6 more | Molecular & Cellular Toxicology

Beyond Respiration: Rethinking CO2 as a Regulator of Cellular Signaling in Microenvironmental Stress and Disease

2025-06-17

Masahiko Shigemura | International Journal of Molecular Sciences

Carbon dioxide (CO2) is a chemically simple molecule with essential roles in biology [...]. Carbon dioxide (CO2) is a chemically simple molecule with essential roles in biology [...].

Expression of Concern: Mitochondrial dynamic modulation exerts cardiometabolic protection in obese insulin-resistant rats

2025-06-01

| PubMed