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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse lipin gene, Lpin1, is important for adipose tissue development and is a candidate gene for insulin resistance. Here, we investigate the adipose tissue expression levels of the human LPIN1 gene in relation to various clinical variables as well as adipocyte function. LPIN1 gene expression was induced at an early step in human preadipocyte differentiation in parallel with peroxisome proliferator-activated receptor gamma. Lipin mRNA levels were higher in fat cells than in adipose tissue segments but showed no difference between subcutaneous and omental depots. Moreover, LPIN1 expression levels were reduced in obesity, improved following weight reduction in obese subjects, and were downregulated in women with the metabolic syndrome. With respect to adipocyte function, adipose LPIN1 gene expression was strongly associated with both basal and insulin-mediated subcutaneous adipocyte glucose transport as well as mRNA levels of glucose transporter 4 (GLUT4). We show that body fat accumulation is a major regulator of human adipose LPIN1 expression and suggest a role of LPIN1 in human preadipocyte as well as mature adipocyte function.
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PMID:A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. 1703 74

The TALLYHO/JngJ (TH) strain is a newly established, polygenic mouse model for type 2 diabetes (T2D) and obesity, and we have previously reported some key physiological features of this model after the overt onset of diabetes. In the present work, we conducted a comprehensive phenotypic characterization of TH in order to completely characterize this new and relevant model for human T2D and obesity. We monitored the development of obesity and diabetes starting at 4 weeks of age by measuring body weight, glucose tolerance, and plasma levels of insulin, glucose, and triglyceride. Additionally, histological alterations in the pancreas and glucose uptake and glucose transporter 4 (GLUT4) content in soleus muscle were also examined. Compared with age- and sex-matched C57BL/6J (B6) mice, both male and female TH mice were significantly heavier, hyperleptinemic, and hyperinsulinemic at 4 weeks of age, without glucose intolerance or hyperglycemia. TH mice maintained higher body weights throughout the study period of 16 weeks. The hyperinsulinemia in TH mice worsened with age, but to a lesser degree in females than in males. Both the male and the female TH mice had enlarged pancreatic islets. Male TH mice showed impaired glucose tolerance at 8 weeks that became more prominent at 16 weeks. Plasma glucose levels continuously increased with age in male TH mice resulting in frank diabetes, while female TH mice remained normoglycemic throughout the study. Impaired glucose tolerance and hyperglycemia in male TH mice were accompanied by impaired 2-deoxyglucose uptake in the soleus muscle at basal and insulin-stimulated states, but without any reduction in GLUT4 content. Interestingly, male TH mice exhibited a drastic elevation in plasma triglyceride levels in the pre-diabetic stage that was maintained throughout the study. These findings suggest that obesity and insulin resistance are an inherent part of the TH phenotype and glucose intolerance is evident preceding progression to overt diabetes in male TH mice.
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PMID:Phenotypic characterization of polygenic type 2 diabetes in TALLYHO/JngJ mice. 1708 13

The insulin-responsive glucose transporter 4 (GLUT4) has a major role in glucose uptake and metabolism in insulin target tissues (i.e. adipose and muscle cells). In these tissues, the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors and the winged-helix-forkhead box class O (FOXO) family of factors are two key families of transcription factors that regulate glucose homeostasis and insulin responsiveness. Type 2 diabetes mellitus and obesity are associated with impaired regulation of GLUT4 gene expression and elevated levels of free fatty acids and proinflammatory factors. Based on our studies of the interplay between PPAR-gamma, FOXO1 and free fatty acids, and inflammation in regulating GLUT4 transcription in sickness and in health, we suggest a novel paradigm to increase insulin sensitivity in bona fide insulin target cells.
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PMID:Transcriptional regulation of the GLUT4 gene: from PPAR-gamma and FOXO1 to FFA and inflammation. 1731 7

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-lambda, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-lambda knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet beta cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.
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PMID:Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. 1764 77

Bis(allixinato)oxovanadium(IV), VO(alx)(2) (alx is 3-hydroxy-5-methoxy-6-methyl-2-pentyl-4-pyrone), has been reported to act as an antidiabetic agent in streptozotocin-induced type-1-like and obesity-linked KKA(y) type 2 diabetic model mice. VO(alx)(2) is also proposed as a candidate agent for treating metabolic syndromes in animals. However, its functional mechanism is yet to be clarified. In this study, we examined whether VO(alx)(2) contributes to both the activation of the insulin signaling cascade that activates glucose transporter 4 (GLUT4) translocation and the regulation of the forkhead box O1 (FoxO1) transcription factor that controls the gene transcription of gluconeogenesis genes. The following three important results were obtained: (1) intracellular vanadium concentration in 3T3-L1 adipocytes is higher after treatment with VO(alx)(2) than with VOSO(4); (2) VO(alx)(2) stimulates the translocation of GLUT4 to the plasma membrane following activation of the tyrosine phosphorylation of the insulin receptor beta-subunit (IRbeta) and insulin receptor substrate (IRS) as well as Akt kinase in 3T3-L1 adipocytes; and (3) the mechanism of inhibition of glucose-6-phosphatase (G6Pase) catalytic subunit gene expression by vanadium is due to disruption of FoxO1 binding with the G6Pase promoter, which indicates that FoxO1 is phosphorylated by VO(alx)(2)-stimulated Akt in HepG2 cells. On the basis of these results, we propose that the critical functions of VO(alx)(2) involve the activation of phosphatidylinositol 3-kinase-Akt signaling through the enhancement of tyrosine phosphorylation of IRbeta and IRS, which in turn transmits the signal to activate GLUT4 translocation, and the regulation of the DNA binding activity of the FoxO1 transcription factor.
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PMID:Action mechanism of bis(allixinato)oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor. 1780 85

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine expression is one of the most important targets for the prevention of obesity and improvement of insulin sensitivity. In this study, we have demonstrated that anthocyanin (cyanidin 3-glucoside; C3G) which is a pigment widespread in the plant kingdom, ameliorates hyperglycemia and insulin sensitivity due to the reduction of retinol binding protein 4 (RBP4) expression in type 2 diabetic mice. KK-A(y) mice were fed control or control +0.2% of a C3G diet for 5 weeks. Dietary C3G significantly reduced blood glucose concentration and enhanced insulin sensitivity. The adiponectin and its receptors expression were not responsible for this amelioration. C3G significantly upregulated the glucose transporter 4 (Glut4) and downregulated RBP4 in the white adipose tissue, which is accompanied by downregulation of the inflammatory adipocytokines (monocyte chemoattractant protein-1 and tumor necrosis factor-alpha) in the white adipose tissue of the C3G group. These findings indicate that C3G has significant potency in an anti-diabetic effect through the regulation of Glut4-RBP4 system and the related inflammatory adipocytokines.
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PMID:Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. 1786 25

Experimental and clinical studies have demonstrated that early postnatal overnutrition represents a risk factor for later obesity and associated metabolic and cardiovascular disturbance. In the present study, we assessed the levels of glucose transporter 4 (GLUT-4), GLUT-1, insulin receptor (IR), IR substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt expression, as well as insulin-stimulated glucose transport and Akt activity in adipocytes from adult rats previously raised in small litters (SL). The normal litter (NL) served as control group. We also investigated glycemia, insulinemia, plasma lipid levels, and glucose tolerance. Our data demonstrated that early postnatal overfeeding induced a persistent hyperphagia accompanied by a significant increase in body weight until 90 days of age. The SL group also presented a significant increase ( approximately 42%) in epidydimal fat weight. Blood glucose, plasma insulin, and lipid levels were similar among the animals from the SL and NL groups. While insulin-stimulated glucose uptake was approximately twofold higher in adipocytes from the NL group, no stimulatory effect was observed in the SL group. The impaired insulin-stimulated glucose transport in adipose cells from the SL rats was associated with a significant decrease in GLUT-4, IRS-1 and PI3K expression, and Akt activity. In contrast, IR and Akt expression in adipocytes was not different between the SL and NL groups. Despite these alterations, our results showed no differences in glucose tolerance test in rats raised under different feeding conditions. Our findings reinforce a potent and long-term effect of neonatal overfeeding, which can program major changes in the metabolic regulatory mechanisms.
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PMID:Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition. 1800 Mar 10

Flaxseed lignan secoisolariciresinol diglucoside (SDG) has been reported to prevent and alleviate lifestyle-related diseases including diabetes and hypercholesterolaemic atherosclerosis. This study assesses the effect of SDG on the development of diet-induced obesity in mice and the effect of the SDG metabolite enterodiol (END) on adipogenesis in 3T3-L1 adipocytes. We compared body weight, visceral fat weight, liver fat content, serum parameters, mRNA levels of lipid metabolism-related enzymes and adiponectin in mice fed either a low-fat diet (5 % TAG), high-fat diet (30 % TAG) or high-fat diet containing 0.5 and 1.0 % (w/w) SDG for 4 weeks. Administration of SDG to mice significantly reduced high-fat diet-induced visceral and liver fat accumulation, hyperlipaemia, hypercholesterolaemia, hyperinsulinaemia and hyperleptinaemia. SDG also suppressed sterol regulatory element binding protein 1c mRNA level in the liver and induced increases in the adiponectin mRNA level in the white adipose tissue and carnitine palmitoyltransferase I mRNA level in the skeletal muscle. Differentiated 3T3-L1 adipocytes were treated with 0, 5, 10 and 20 mumol/l END and then assayed for mRNA expression of adipogenesis-related genes and DNA binding activity of PPARgamma to the PPAR response element consensus sequence. END induced adipogenesis-related gene mRNA expression including adiponectin, leptin, glucose transporter 4 and PPARgamma, and induced PPARgamma DNA binding activity in 3T3-L1 adipocytes. In conclusion, SDG induced adiponectin mRNA expression and showed beneficial effects on lipid metabolism in diet-induced obesity in mice. Flaxseed lignans are suggested to regulate adipogenesis-related gene expressions through an increase in PPARgamma DNA binding activity.
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PMID:Flaxseed lignan attenuates high-fat diet-induced fat accumulation and induces adiponectin expression in mice. 1825 24

Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage and the mechanisms involved during obesity is poorly understood. Through proteomics and microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects obesity and its related adipose inflammation. Herein we show that the levels of LCN2 mRNA are dramatically increased in adipose tissue and liver of ob/ob mice and primary adipose cells isolated from Zucker obese rats, and thiazolidinedione administration reduces LCN2 expression. Interestingly, addition of LCN2 induces mRNA levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) and adiponectin. Reducing LCN2 gene expression causes decreased expression of PPARgamma and adiponectin, slightly reducing insulin-stimulated Akt2 phosphorylation at Serine 473 in 3T3-L1 adipocytes. LCN2 administration to 3T3-L1 cells attenuated TNFalpha-effect on glucose uptake, expression of PPARgamma, insulin receptor substrate-1, and glucose transporter 4, and secretion of adiponectin and leptin. When added to macrophages, LCN2 suppressed lipopolysaccharide-induced cytokine production. Our data suggest that LCN2, as a novel autocrine and paracrine adipokine, acts as an antagonist to the effect of inflammatory molecules on inflammation and secretion of adipokines.
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PMID:The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. 1829 40

The insulin-responsive glucose transporter 4 (GLUT4) plays a key role in glucose uptake and metabolism in insulin target tissues. Being a rate-limiting step in glucose metabolism, the expression and function of the GLUT4 isoform has been extensively studied and found to be tightly regulated at both mRNA and protein levels. Adaptation to states of enhanced metabolic demand is associated with increased glucose metabolism and GLUT4 gene expression, whereas states of insulin resistance such as type 2 diabetes mellitus (DM2), obesity, and aging are associated with impaired regulation of GLUT4 gene expression and function. The present review focuses on the interplay among hormonal, nutritional, and transcription factors in the regulation of GLUT4 transcription in health and sickness.
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PMID:Transcriptional regulation of the insulin-responsive glucose transporter GLUT4 gene: from physiology to pathology. 1849 67


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