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

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.
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PMID:Molecular mechanisms of insulin resistance and the role of the adipocyte. 1112 35

Myostatin is a TGF-beta family member that acts as a negative regulator of muscle growth. Mice lacking the myostatin gene (Mstn) have a widespread increase in skeletal muscle mass resulting from a combination of muscle fiber hypertrophy and hyperplasia. Here we show that Mstn-null mice have a significant reduction in fat accumulation with increasing age compared with wild-type littermates, even in the setting of normal food intake (relative to body weight), normal body temperature, and a slightly decreased resting metabolic rate. To investigate whether myostatin might be an effective target for suppressing the development of obesity in settings of abnormal fat accumulation, we analyzed the effect of the Mstn mutation in two genetic models of obesity, agouti lethal yellow (A(y)) and obese (Lep(ob/ob)). In each case, loss of Mstn led to a partial suppression of fat accumulation and of abnormal glucose metabolism. Our findings raise the possibility that pharmacological agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type 2 diabetes.
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PMID:Suppression of body fat accumulation in myostatin-deficient mice. 1187 67

Diabetes mellitus has attained epidemic proportions worldwide. It is suggested that resistin (also called Fizz 3), a cysteine. rich-protein may represent a link between obesity and insulin resistance. Uncoupling proteins are candidate genes for human obesity or type 2 diabetes mellitus. Amylin has a vital role in regulating blood glucose concentration following meals. Gluco watch biographers are safe and effective device to measure glucose every 20 minutes. Islet transplantation has had a remarkable preliminary success. Protein kinase Cbeta inhibitor was shown to reduce albuminuria and decrease statement of TGFbeta and various extracellular matrix proteins in diabetic rats.
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PMID:Current and future perspective in the management of diabetes. 1240 80

Protein kinase C theta (PKC-theta) is the PKC isoform predominantly expressed in skeletal muscle, and it is supposed to mediate many signals necessary for muscle histogenesis and homeostasis, such as TGFbeta, nerve-dependent signals and insulin. To study the role of PKC-theta in these mechanisms we generated transgenic mice expressing a "kinase dead" mutant form of PKC-theta (PKC-thetaK/R), working as "dominant negative," specifically in skeletal muscle. These mice are viable and fertile, however, by the 6-7 months of age, they gain weight, mainly due to visceral fat deposition. Before the onset of obesity (4 months of age), they already show increased fasting and fed insulin levels and reduced insulin-sensitivity, as measured by ipITT, but normal glucose tolerance, as measured by ipGTT. After the 6-7 months of age, transgenic mice develop hyperinsulinemia in the fasting and fed state. The ipGTT revealed in the transgenic mice both hyperglycemia and hyperinsulinemia. At the molecular level, impaired activation of the IR/IRS/PI3K pathway and a significant decrease both in the levels and in insulin-stimulated activation of the serine/threonine kinase Akt were observed. Taken together these data demonstrate that over-expression of dominant negative PKC-theta in skeletal muscle causes obesity associated to insulin resistance, as demonstrated by defective receptor and post-receptorial activation of signaling cascade.
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PMID:Transgenic mice with dominant negative PKC-theta in skeletal muscle: a new model of insulin resistance and obesity. 1276 44

Several epidemiological studies have supported the concept that high energy intake, obesity, and/or hyperinsulinemia are risk factors for colon cancer. Previously, it was shown that Zucker obese rats are more sensitive to chemically induced colon cancer than their lean counterparts. The present study investigated whether moderate (20-25%) dietary energy restriction (ER) would attenuate colon carcinogenesis in the Zucker obese rat model. Six-week-old Zucker obese (fa/fa) rats and lean (Fa/Fa) rats received s.c. injections of azoxymethane at a dose of 10 mg/kg body weight once weekly for 2 weeks. A week later, obese rats (n = 16) were assigned to an ER diet (Ob-ER group), based on a low-fat AIN-93G semisynthetic diet. The remaining obese and lean rats (n = 16 rats/group) were fed the low-fat diet ad libitum (Ob group and Ln group, respectively). All rats were euthanized after 8 weeks, and their colons were assessed for aberrant crypt foci (ACF; n = 8/group) or for the expression of transforming growth factor (TGF)-beta and cyclooxygenase (COX) isoforms at the protein and mRNA transcript levels (n = 8/group). Ob rats had a higher number of advanced ACF (crypt multiplicity >or=7) than Ln rats. Dietary ER significantly reduced the appearance of advanced ACF in Ob-ER rats without significantly affecting the blood insulin level or body weights. TGF-beta and COX isoforms were differentially expressed in the colonic mucosae of Ob and Ln rats. Dietary ER significantly reduced TGF-beta1/beta2 and COX-1/2 protein expression in obese rats. This study is the first to demonstrate that moderate ER attenuated TGF-beta and COX protein expression and the carcinogenic process in Zucker obese rats. These findings provide insights leading to the proposal that the mechanism(s) underlying the early events of colon carcinogenesis in Zucker obese rats may extend beyond the role of excessive body weight and hyperinsulinemia per se.
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PMID:Energy restriction reduces the number of advanced aberrant crypt foci and attenuates the expression of colonic transforming growth factor beta and cyclooxygenase isoforms in Zucker obese (fa/fa) rats. 1458 51

Insulin resistance is associated with a low chronic inflammatory state. In this study we investigated the relationship between impaired insulin sensitivity and selected markers of inflammation and thrombin generation in obese healthy women. We examined 32 healthy obese women (body mass index > or = 28), with normal insulin sensitivity (NIS, n = 14) or impaired insulin sensitivity (n = 18), and 10 nonobese women (body mass index < 25). Impaired insulin sensitivity patients had significantly higher levels of C-reactive protein (CRP), TGF-beta 1, plasminogen activator inhibitor-1 (PAI-1), activated factor VII (VIIa), and prothrombin fragment 1 + 2 (F1 + 2) compared with either control subjects or NIS patients. On the other hand, NIS patients had higher CRP, TGF-beta 1, PAI-1, and factor VIIa, but not F1 + 2, levels than controls. Significant inverse correlations were observed between the insulin sensitivity index and TGF-beta 1, CRP, PAI-1, factor VIIa, and F1 + 2 levels. Moreover, significant direct correlations were noted between TGF-beta 1 and CRP, PAI-1, factor VIIa, and F1 + 2 concentrations. Finally, multiple regressions revealed that TGF-beta 1 and the insulin sensitivity index were independently related to F1 + 2. Our results are the first to document an in vivo relationship between insulin sensitivity and coagulative activation in obesity. The elevated TGF-beta 1 levels detected in the obese population may provide a biochemical link between insulin resistance and an increased risk for cardiovascular disease.
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PMID:Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women. 1460 68

The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA+cells were significantly more frequent and expression of TGF-beta and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/N-cp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.
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PMID:Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes. 1476 89

In the present study, we investigated, using custom dog cDNA arrays, the time course of transcriptional changes in the left ventricle of dogs fed a normal diet or a high-fat diet (HFD) for 9-24 wk. Array hybridizations were performed with complex probes representing mRNAs expressed in left ventricles from obese hypertensive and lean control dogs. We identified 63 differentially expressed genes, and expression of 17 of 20 randomly chosen genes was confirmed by real-time PCR. Transcripts were categorized into groups involved in metabolism, cell signaling, tissue remodeling, ionic regulation, cell proliferation, and protein synthesis. Hierarchical clustering indicated that the pattern of coregulated genes depends on duration of the HFD, suggesting that HFD-induced obesity hypertension is associated with continuous cardiac transcriptome adaptation despite stability of both body weight and blood pressure. GenMAPP analysis of the data pointed out the crucial importance of the ventricle TGF-beta pathway. Our results suggest that this system may be involved in molecular remodeling during HFD and in changes observed in the transcription profile, reflecting functional and morphological abnormalities that arise during prolonged HFD. These results also suggest some novel regulatory pathways for cardiac adaptation to obesity.
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PMID:Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs. 1522 82

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
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PMID:Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. 1525 62

Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT(1)) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-beta(1), left ventricular collagen and mural immunoreactivity for PAI-1, TGF-beta and collagen type 1. The c-Jun NH(2)-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-beta(1) with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.
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PMID:Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. 1527 22


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