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

Brown adipose and muscle tissues can increase energy expenditure via adaptive thermogenesis, thereby protecting against obesity. Mouse peroxisome proliferator activated receptor gamma coactivator 1 (Pgc1) has been reported to enhance the expression of uncoupling protein-1, a key mediator of thermogenesis in brown adipose tissue (Puigserver et al., 1998, Cell 92, 829-839). We report here the characterization of the human PPARGC1 gene. PPARGC1 spans a genomic region of approximately 67 kb, is composed of 13 exons, and encodes a 91-kDa protein that exhibits 94% amino acid identity with the mouse ortholog. mRNA species, transcribed from the TATA-less promoter, are 6.4 and 5.3 kb in length due to utilization of two polyadenylation signals. Northern blotting revealed expression of both transcripts in heart, skeletal muscle, and kidney and to a lesser extent in liver, brain, and pancreas as well as in the perirenal adipose tissue of a pheochromocytoma patient. PPARGC1 was mapped to chromosome 4p15.1, a region that has been associated with basal insulin levels in Pima Indians. Hence, PPARGC1 expression might influence insulin sensitivity as well as energy expenditure, thereby contributing to the development and pathophysiology of human obesity.
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PMID:Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. 1058 75

Studies from the past several years have revealed that adipogenesis is controlled by an interplay of transcription factors, including members of the CCAAT/enhancer binding protein family and peroxisome proliferator activated receptor gamma. In addition to providing a new understanding of this aspect of the energy balance systems, these factors provide potential new targets for therapeutic intervention in metabolic diseases, such as obesity and type 2 diabetes mellitus.
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PMID:Transcriptional activation of adipogenesis. 1060 Jul 10

Over-eating and physical inactivity in combination with genetic factors play the most important roles in the development of over weight in humans. The common genetic components behind excess accumulation of body fat are so far unknown. Studies of candidate genes indicate that most of the genes that associate with obesity control important functions of adipose tissue as well. Furthermore, structural variations in these genes may alter adipose tissue function in a way that promotes obesity. The genes which both are functional in human adipose tissue and associate with obesity are: hormone sensitive lipase, beta2 and beta3-adrenoceptors, tumor necrosis factor alpha, low density lipoprotein receptor, uncoupling protein-1 and peroxisome proliferator activated receptor gamma-2. Other genes are mostly important for obesity among women (for example beta2 -and beta3-adrenoceptors, low density lipoprotein receptor and tumor necrosis factor alpha). Some of these genes may promote obesity by gene-gene interactions (for example beta3-adrenoceptors and uncoupling protein-1) or gene-environmental interactions (for example beta2-adrenoceptors and physical activity). Few genes with no known function in adipose tissue have shown a firm association with excess body fat. The latter suggests that the important human obesity genes also control adipose tissue function. Therefore it might be of value to focus the further hunt for obesity genes on the fat tissue.
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PMID:Hunting for human obesity genes? Look in the adipose tissue! 1112 44

Fat build-up is determined by the balance between lipogenesis and lipolysis/fatty acid oxidation. In the past few years, our understanding of the nutritional, hormonal and particularly transcriptional regulation of lipogenesis has expanded greatly. Lipogenesis is stimulated by a high carbohydrate diet, whereas it is inhibited by polyunsaturated fatty acids and by fasting. These effects are partly mediated by hormones, which inhibit (growth hormone, leptin) or stimulate (insulin) lipogenesis. Recent research has established that sterol regulatory element binding protein-1 is a critical intermediate in the pro- or anti-lipogenic action of several hormones and nutrients. Another transcription factor implicated in lipogenesis is the peroxisome proliferator activated receptor gamma. Both transcription factors are attractive targets for pharmaceutical intervention of disorders such as hypertriglyceridemia and obesity.
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PMID:Mechanisms of nutritional and hormonal regulation of lipogenesis. 1130 47

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity. These include leptin, tumor necrosis factor alpha, Acrp30/adiponectin/adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor gamma, a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans.
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PMID:Resistin and obesity-associated insulin resistance. 1175 Aug 58

Obesity and diabetes have reached epidemic proportions worldwide. The antidiabetic thiazolidinedione (TZD) drugs are insulin-sensitizing agents now widely used in the treatment of type 2 diabetes. TZDs are ligands for the nuclear hormone receptor peroxisome proliferator activated receptor gamma, which is a master regulator of adipogenesis and adipocyte metabolism. The molecular mechanisms by which TZDs improve insulin sensitivity have not been fully identified. Here we consider a novel secreted factor first identified as a TZD-suppressible gene in mouse adipocytes, called resistin, and discuss what is currently known about resistin regulation and function in mouse and human.
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PMID:Resistin: molecular history and prognosis. 1270 Aug 89

Selective cyclo-oxygenase-2 (COX-2) inhibitors are nonsteroidal antiinflammatory drugs used in the management of inflammatory diseases. We demonstrate here that inhibition of the COX-2 enzyme impairs adipocyte differentiation. The inhibition of adipogenesis occurs in the early clonal expansion phase. In particular, COX-2 inhibition limits cell cycle reentry required before terminal adipocyte differentiation. This inhibition of adipogenesis is independent of the production of the peroxisome proliferator activated receptor gamma ligand prostaglandin J2, but dependent on the production of proliferative prostaglandins, such as prostaglandin E2. Modulation of the activity of the COX-2 enzyme via COX-2 selective inhibitors might open up new perspectives in the control of obesity and related metabolic diseases.
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PMID:Selective cyclo-oxygenase-2 inhibitors impair adipocyte differentiation through inhibition of the clonal expansion phase. 1283 47

It is now over 10 years since the discovery of peroxisome proliferator activated receptor gamma (PPAR gamma) and its unique role in adipogenesis. The subsequent identification of PPAR gamma as the target of insulin sensitizing drugs certified this ligand-regulated transcription factor as an exciting link between adipocyte biology and peripheral insulin resistance. Here, I summarize the great progress that has been made over the past decade in elucidating the biology of PPAR gamma and its role in adipogenesis and glucose metabolism. Prospects for future research leading to new therapies for obesity and diabetes are also discussed.
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PMID:PPAR gamma, 10 years later. 1573 30

Insulin resistance is the earliest observable abnormality in individuals who are predisposed to, and who later develop type 2 diabetes mellitus. We hypothesize that saturation of the subcutaneous fat depot is the primary event in the pathophysiology of insulin resistance in the majority of patients and postulate that this seminal event may lead to the development of hypertension, hypertriglyceridemia and depressed HDL levels (i.e., the metabolic syndrome). Our hypothesis has the following clinical implications: (1) differing responses to weight loss may be seen with regards to insulin resistance depending on the size of the fat depot; individuals with small fat depots having to maintain an extremely low body mass to preserve an insulin sensitive phenotype while individuals with a large fat depot may become insulin sensitive even when still clinically obese with some amount of weight loss; (2) peroxisome proliferator activated receptor gamma agonists, such as thiazoledinediones which expand the subcutaneous fat depot, may be especially useful in improving insulin resistance in individuals with small fat depots; (3) expanding alternate storage sites for triglycerides by a variety of techniques, such as resistance training-induced muscle hypertrophy, may also improve insulin resistance; (4) drugs, such as beta 3 adrenergic receptor agonists which promote lipolysis and have been suggested as possible agents in the treatment of obesity may actually increase insulin resistance by releasing free fatty acids into the circulation. Similarly, inhibitors of the beta oxidation of free fatty acids (e.g., carnitine palmitoyl transferase inhibitors) may also actually cause insulin resistance by sparing fat from oxidation and thus worsening fat depot saturation and (5) liposuction, by reducing the size of the subcutaneous fat depot may actually worsen insulin resistance, thus increasing the risk of type 2 diabetes mellitus.
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PMID:The role of saturation of fat depots in the pathogenesis of insulin resistance. 1636 Feb 89

The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARgamma) critically regulates adipogenesis and lipogenesis. Obesity is closely associated with increased oxidative stress, and pharmacological activation of PPARgamma by its ligands significantly suppresses oxidative stress in cultured adipocytes. On the other hand, a PPARgamma2(Pro12Ala) polymorphism, which decreases receptor transcription activity, is associated with lower body mass index and increased insulin sensitivity in humans. This mutation is also found to be positively associated with increased human lifespan. Here we show that adipose tissue-specific PPARgamma heterozygous mice, which exhibit significant improvement in insulin sensitivity in skeletal muscle, show increased resistance to paraquat-induced oxidative stress. The enhanced oxidative stress tolerance is associated with significant upregulation of antioxidant genes in white adipose tissue and skeletal muscle whereas prooxidant genes are not changed. This is also associated with a significant increase in adipose tissue of Foxo3a, a transcription factor that is known to regulate clearance of reactive oxygen species. Consistently, Foxo3a dependent genes are significantly upregulated in adipose tissue. These data implicate adipose tissue PPARgamma in the regulation of oxidative stress, which may underlie extended lifespan in humans bearing PPARgamma2(Pro12Ala) mutation.
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PMID:Adipose tissue-specific PPARgamma deficiency increases resistance to oxidative stress. 1808 18


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