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

The ongoing global explosion in the incidence of obesity has focused attention on the development of adipose cells. Severe obesity is the result of an increase in fat cell size in combination with increased fat cell number. New fat cells arise from a pre-existing pool of adipose stem cells that are present irrespective of age. The development of established preadipocyte cell lines has facilitated the study of different steps leading to terminal differentiation. However, these systems are limited for studying early events of differentiation as they represent cells which are already determined for the adipogenic lineage. In vitro differentiation of mouse embryonic stem (ES) cells towards the adipogenic lineage provides an alternative source of adipocytes for study in tissue culture and offers the possibility to investigate regulation of the first steps of adipose cell development. In this review, we describe the sequential requirement of retinoic acid and PPARgamma during adipogenesis in ES cells. Stimulation of ES cells with synthetic retinoids which are selective ligands of the retinoic acid receptor isotypes allowed the investigation of the contribution of the different retinoic receptors on the RA-dependent differentiation. The effects of thiazolidinediones, a new class of pharmacological agents used for the treatment of type 2 diabetes, and of statins, drugs used in therapy for lowering cholesterol, on the differentiation of ES cells into adipocytes or osteoblasts are described. Finally, we propose a model in which PPARgamma plays a key role in the decision of stem cells to undergo differentiation into adipocytes or osteoblasts, two closely related lineages.
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PMID:Differentiation of embryonic stem cells for pharmacological studies on adipose cells. 1264 82

Thiazolidinediones are used to treat type 2 diabetes mellitus because they decrease plasma glucose, insulin, triglyceride, and fatty acid levels. Thiazolidinediones are agonists for peroxisome proliferator-activated receptor gamma, a nuclear receptor that is highly expressed in fat tissue. We identify glyceroneogenesis as a target of thiazolidinediones in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by thiazolidinediones occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The increase in glyceroneogenesis is a result of the induction of its key enzyme, phosphoenolpyruvate carboxykinase, whose gene expression is peroxisome proliferator-activated receptor gamma-dependent in adipocytes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma. The importance of such a fatty acid re-esterification process in the control of lipid homeostasis is highlighted by the existence of a second thiazolidinedione-induced pathway involving glycerol kinase. We show that glyceroneogenesis accounts for at least 75% of the whole thiazolidinedione effect. Because elevated plasma fatty acids promote insulin resistance, these results suggest that the glyceroneogenesis-dependent fatty acid-lowering effect of thiazolidinediones could be an essential aspect of the antidiabetic action of these drugs.
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PMID:Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells. 1264 61

Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and beta-cell dysfunction, including tumour necrosis factor alpha (TNF-alpha), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor gamma, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve beta-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-alpha and FFAs.
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PMID:The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. 1267 Jul 40

Although peroxisome proliferator-activated receptor (PPAR)gamma agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARgamma agonist, pioglitazone, and a PPARalpha agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARgamma agonist-treated groups. Also, PPARgamma agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARgamma and -alpha agonists. We conclude that combination therapy with PPARgamma and PPARalpha agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.
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PMID:Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. 1267 49

Peroxisome proliferator activated receptors (PPARs) are fertile targets for drug discovery. They are targets for two widely used classes of drugs, the fibrates and thiazolidinediones. Remarkable advances have been made in our understanding of the mechanism of action of these receptors over the last 10 years. Further research and development of the three identified PPARs, PPARalpha, PPARbeta and PPARgamma, may help develop more efficacious drugs in the treatment of dyslipidemia, cardiovascular diseases, obesity and diabetes. (c) 2002 Prous Science. All rights reserved.
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PMID:PPARs: Versatile Targets for Future Therapy for Obesity, Diabetes and Cardiovascular Diseases. 1267 21

The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)alpha and LXR beta have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR/retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.
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PMID:Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. 1269 4

In contrast to the well-established roles of PPARgamma and PPARalpha in lipid metabolism, little is known for PPARdelta in this process. We show here that targeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity. Importantly, these animals are completely resistant to both high-fat diet-induced and genetically predisposed (Lepr(db/db)) obesity. As predicted, acute treatment of Lepr(db/db) mice with a PPARdelta agonist depletes lipid accumulation. In parallel, PPARdelta-deficient mice challenged with high-fat diet show reduced energy uncoupling and are prone to obesity. In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. Our findings suggest that PPARdelta serves as a widespread regulator of fat burning and identify PPARdelta as a potential target in treatment of obesity and its associated disorders.
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PMID:Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. 1270 65

Lipid and carbohydrate homeostasis in higher organisms is under the control of an integrated system that has the capacity to rapidly respond to metabolic changes. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. The three PPAR subtypes, alpha, gamma, and delta, have distinct expression patterns and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. Recent advances in identifying selective ligands in conjunction with microarray analyses and gene targeting studies have helped delineate the subtype-specific functions and the therapeutic potential of these receptors. PPARalpha potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates (e.g. fenofibrate and gemfibrozil), whereas PPARgamma is essential for adipocyte differentiation and mediates the activity of the insulin-sensitizing thiazolidinediones (e.g. rosiglitazone and pioglitazone). Recent evidence suggests that PPARdelta may be important in controlling triglyceride levels by sensing very low-density lipoprotein. Thus, uncovering the regulatory mechanisms and transcriptional targets of the PPARs will continue to provide insight into the pathogenesis of metabolic diseases and, at the same time, offer valuable information for rational drug design.
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PMID:Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. 1274 75

Mutations in the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene may cause obesity and insulin resistance. Therefore we investigated whether known variants in the PPAR-gamma 2 gene are associated with obesity and extreme insulin resistance in obese patients with impaired glucose tolerance (IGT). The Pro115 Gln, Pro12Ala, Pro467Leu, Val290Met and a silent polymorphism C478 T were examined in 48 subjects with IGT and insulin resistance (IR), characterized by euglycemic hyperinsulinemic clamps, and in 52 healthy insulin sensitive (IS) controls. We found one proband in the IR group with the Pro115 Gln variant. This subject showed a lower whole body glucose uptake (18 micromol/kg per min) compared to the entire IR group (29 micromol/kg per min). The body weight of the proband (BMI 28.5 kg/m2) was within the average of the IR group (30.3 +/- 0.8 kg/m2). The Pro12Ala variant was not associated with differences in BMI, in the degree of insulin resistance between the IR and IS group. The Pro467Leu, Val290Met mutations and the silent polymorphism CAC478CAT were not detected in any group. In conclusion, the Pro115 Gln variant, but not the Pro12Ala mutation in the PPAR-gamma 2 gene, could be a rare cause of severe insulin resistance.
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PMID:Analysis of the relationship between PPAR-gamma 2 gene variants and severe insulin resistance in obese patients with impaired glucose tolerance. 1274 59

This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and in vivo in IR obese mice (ob/ob). Thus, MCP-1 resembles other previously described genes (e.g., PAI-1 and SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues. In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (LpL, adipsin, GLUT-4, aP2, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.
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PMID:Monocyte chemoattractant protein 1 in obesity and insulin resistance. 1275 99


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