scholarly journals Adipocyte-Specific Ablation Of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome In Aging Mice

2021 ◽  
Author(s):  
Keyun Chen ◽  
Alejandra De Angulo ◽  
Xin Guo ◽  
Aditya More ◽  
Scott A. Ochsner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Composition ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Later Life ◽  
And Function

ABSTRACTObjectiveAlthough PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of age-associated metabolic syndrome.MethodsWe generated mice with adipocyte specific PU.1 knockout, assessed metabolic changes in young and aged PU.1fl/fl (control) and AdipoqCre PU.1fl/fl(aPU.1KO) mice, including body weight, body composition, energy expenditure and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice.ResultsaPU.1KO mice have elevated energy expenditure at a young age and decreased adiposity and increased insulin sensitivity in later life. Corroborating these observations, transcriptional network analysis indicated the existence of validated, aPU.1-modulated regulatory hubs that direct inflammatory and thermogenic gene expression programs.ConclusionsOur data provide evidence for a previously uncharacterized role of PU.1 in the development of age-associated obesity and insulin resistance.

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

scholarly journals Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

2019 ◽  
Vol 20 (9) ◽  
pp. 2109 ◽  
Author(s):  
Arulkumar Nagappan ◽  
Jooyeon Shin ◽  
Myeong Ho Jung
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Hepatic Insulin Resistance ◽  
Leptin Resistance ◽  
Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

scholarly journals Global metabolic consequences of the chromogranin A-null model of hypertension: transcriptomic detection, pathway identification, and experimental verification

2010 ◽  
Vol 40 (3) ◽  
pp. 195-207 ◽  
Author(s):  
Ryan S. Friese ◽  
Jiaur R. Gayen ◽  
Nitish R. Mahapatra ◽  
Geert W. Schmid-Schönbein ◽  
Daniel T. O'Connor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Chromogranin A ◽  
Secretory Granules ◽  
Cholesterol Biosynthesis ◽  
Hepatic Cholesterol ◽  
The Metabolic Syndrome ◽  
Insight Into

Chromogranin A (CHGA) has a crucial role in formation of regulated secretory granules in neuroendocrine tissues and is also a prohormone that is proteolytically processed into peptides with diverse and complex actions. CHGA and several of its peptide products, including catestatin and pancreastatin, are implicated in pathogenesis of essential hypertension, insulin resistance, and the metabolic syndrome. The Chga knockout mouse (Chga KO) displays severe hypertension coupled with reduction in size, number, and density of regulated secretory granules. We performed genome-wide transcriptome profiling in Chga KO adrenal gland and liver for insight into biochemical and physiological systems altered in this monogenic mouse model of hypertension. Adrenal gene expression pathway prediction of enhanced insulin sensitivity ( P = 0.03) in Chga KO was confirmed with glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) measurements: blood glucose was normal in Chga KO, blood insulin was reduced 4.5-fold ( P < 0.0001), and HOMA-IR was decreased 3.8-fold ( P < 0.002). Remarkably, such observations conclusively dissociate fundamental features of the metabolic syndrome in this monogenic hypertension model. Exogenous pancreastatin treatment restored insulin sensitivity in the Chga KO to near-normal levels. Gene expression predictions of decreased adrenal cholesterol biosynthesis ( P < 0.001) and increased hepatic cholesterol biosynthesis ( P < 0.001) were verified with tissue total cholesterol assays: Chga KO adrenal cholesterol decreased 1.8-fold ( P = 0.039) and hepatic cholesterol increased 1.8-fold ( P = 0.018). Transcriptional regulatory network prediction identified sets of transcription factors that may provide insight into the unclear mechanistic links among CHGA, cholesterol, insulin sensitivity, and the metabolic syndrome. These experiments demonstrate, for the first time, that genetic variation at the CHGA locus impacts insulin sensitivity and tissue cholesterol levels in an intact, living organism. The Chga KO may constitute a unique model for studying the relationship between the CHGA locus and disease phenotypes of the metabolic syndrome.

scholarly journals Low Total Testosterone Levels are Associated With the Metabolic Syndrome in Elderly Men: The Role of Body Weight, Lipids, Insulin Resistance, and Inflammation; The Ikaria Study

2013 ◽  
Vol 10 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Christina Chrysohoou ◽  
Demosthenes Panagiotakos ◽  
Christos Pitsavos ◽  
Gerasimos Siasos ◽  
Evangelos Oikonomou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Weight ◽  
Total Testosterone ◽  
Elderly Men ◽  
Testosterone Levels ◽  
The Metabolic Syndrome

scholarly journals A minor role for lipocalin 2 in high-fat diet-induced glucose intolerance

2011 ◽  
Vol 301 (5) ◽  
pp. E825-E835 ◽  
Author(s):  
Lucy S. Jun ◽  
C. Parker Siddall ◽  
Evan D. Rosen
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Phenotype ◽  
Chow Diet ◽  
High Fat

Adipose tissue controls energy homeostasis and systemic insulin sensitivity through the elaboration of a series of cytokines and hormones, collectively termed “adipokines.” We and others have identified Lcn2 as a novel adipokine, but its exact role in obesity-induced insulin resistance remains controversial. The aim of this study was to examine the metabolic phenotype of Lcn2−/− mice to clarify the role of Lcn2 in metabolism. Male and female Lcn2−/− and wild-type (WT) littermates were placed on either chow or high-fat diet (HFD) to characterize their metabolic phenotype. Studies included body weight and body composition, glucose and insulin tolerance tests, and adipokine expression studies in serum and in white adipose tissue (WAT). Neither chow nor HFD cohorts showed any differences in body weight or body composition. Chow-fed Lcn2−/− mice did not exhibit any difference in glucose homeostasis compared with WT mice. Fasting serum glucose levels were lower in the chow-fed Lcn2−/− mice, but this finding was not seen in the HFD cohort. Serum adiponectin, leptin, resistin, and RBP4 levels were not different between WT and Lcn2−/− on chow diet. HFD-fed male Lcn2−/− mice did display a small improvement in glucose tolerance, but no difference in insulin sensitivity was seen in either male or female Lcn2−/− mice on HFD. We conclude that the global ablation of Lcn2 has a minimal effect on obesity-associated glucose intolerance but does not appear to affect either age- or obesity-mediated insulin resistance in vivo.

Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies

2006 ◽  
Vol 8 (27) ◽  
pp. 1-12 ◽  
Author(s):  
Francis Vasseur ◽  
David Meyre ◽  
Philippe Froguel
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Vascular Complications ◽  
Physiological Role ◽  
Nucleotide Polymorphisms ◽  
The Metabolic Syndrome ◽  
And Function

Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity.

scholarly journals Myocardial remodeling in rats with metabolic syndrome: role of Rho-kinase mediated insulin resistance.

2012 ◽  
Vol 59 (2) ◽  
Author(s):  
Chuan-Bao Li ◽  
Xiao-Xing Li ◽  
Yu-Guo Chen ◽  
Hai-Qing Gao ◽  
Cheng-Mei Bao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Critical Role ◽  
Rho Kinase ◽  
Myocardial Damage ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protein Levels ◽  
Transmission Electron ◽  
And Function

Insulin resistance (IR) plays a critical role in metabolic syndrome (MS). Previous studies have demonstrated that activated ROCK is increased in MS patients. However, the effect of Rho-kinase (ROCK) on IR has not been definitely determined. Thus, the aims of the present study were to determine whether ROCK activation induces IR or affects myocardial structure and function, as well as the possible mechanisms underlying this process. Wistar rats fed high fat, high glucose and high salt diet sewed as model of MS and we used transmission electron microscopy, echocardiogram technology, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify any myocardial damage. The protein levels of MYPT-1 (characteristic of ROCK activation), IRS-1 and AKT were analyzed by immunohistochemistry and Western blotting. In hearts from MS rats, we found increased protein levels of phospho-MYPT-1 and phospho-IRS-1 (Ser307) and decreased phospho-AKT compared to levels in normal rats. In conclusion, the results suggest that ROCK-mediated IR is involved in the development of myocardial impairments in MS rats and that this effect is mediated probably via the IRS-1/PI3-kinase/AKT pathway.

Low doses of cocoa extract supplementation ameliorate diet-induced obesity and insulin resistance in rats

2019 ◽  
Vol 10 (8) ◽  
pp. 4811-4822 ◽  
Author(s):  
Paula Aranaz ◽  
Ana Romo-Hualde ◽  
David Navarro-Herrera ◽  
María Zabala ◽  
Miguel López-Yoldi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Body Weight Gain ◽  
Liver Steatosis ◽  
Low Doses ◽  
Diet Induced Obesity

Supplementation with low doses of a cocoa extract induces metabolic benefits in the prevention of metabolic syndrome in rats, reducing body-weight gain, visceral adiposity and liver steatosis and improving insulin sensitivity and glucose tolerance.

scholarly journals The Metabolic Significance of Leptin in Humans: Gender-Based Differences in Relationship to Adiposity, Insulin Sensitivity, and Energy Expenditure*

1997 ◽  
Vol 82 (4) ◽  
pp. 1293-1300 ◽  
Author(s):  
Adele Kennedy ◽  
Thomas W. Gettys ◽  
Patricia Watson ◽  
Penny Wallace ◽  
Elizabeth Ganaway ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Body Composition ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Body Fat ◽  
Dependent Diabetes Mellitus ◽  
Men And Women ◽  
Serum Leptin ◽  
Gender Based

Abstract Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17–54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P &lt; 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women[ leptin = 1.815 (BMI) − 31.103 in women; leptin = 0.534 (BMI) − 8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat) − 24.817 in women; leptin = 0.402 (% body fat) − 3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = −0.57; P &lt; 0.0001) and high waist to hip ratio (r = 0.75; P &lt; 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.

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