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

Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O(2)) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPAR gamma 2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O(2)-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O(2) sensing may be used to inhibit adipogenesis and control obesity.
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PMID:Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. 1187 38

Combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome or syndrome X. Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. Major signaling pathways coupling transcription factors to extracellular stimuli are the MAP kinase cascades. We have recently shown that SREBPs appear to be substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly syndrome X. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression.
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PMID:SREBP-1: gene regulatory key to syndrome X? 1207 31

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. Since their discovery in the beginning of the nineties the three isoforms (PPARalpha, beta/delta and gamma, encoded by different genes) have been implicated in the regulation of almost every single aspect of lipid metabolism and, consequently, in diseases that involve disturbances in lipid metabolism (obesity, diabetes, atherosclerosis, cardiac failure). Although their prominent role in these processes has hardly been disputed, the way in which the activity of these transcription factors is regulated under physiological and pathological conditions awaits further clarification. An unresolved issue has been the nature of the natural ligand of these receptors. Biochemical studies have shown that the PPAR isoforms are rather promiscuous with respect to ligand binding, with a large variety of naturally occurring lipid-like substances acting as low-affinity ligands. More recently this concept has been confirmed by crystallographic studies on the ligand-binding pocket. In addition to ligand availability, the trans-activating capacity likely depends on phosphorylation status of the PPARs and on the recruitment of auxiliary proteins (co-activators and corepressors). Accordingly, the biological activity of these key-regulators of metabolism is controlled at multiple levels, which enables each tissue to fine tune its metabolic machinery to the demands of the body in a specific fashion.
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PMID:Peroxisome proliferator-activated receptors: lipid binding proteins controling gene expression. 1247 78

Adipogenesis is the process by which mature fat cells are formed from pre-adipocytes. Adipogenesis has come under increasing scrutiny not only because the availability of reliable in vitro models makes it an attractive choice for developmental studies, but also because adipocytes are increasingly recognized as major players in a variety of physiological and pathophysiological states, such as obesity and type 2 diabetes. Adipocytes develop from mesenchymal stem cell precursors that are characterized by multipotency. Under the influence of various cues, these cells become committed to the adipocyte lineage. Further hormonal stimulation recruits these pre-adipocytes to accumulate lipid, express fat-specific markers, and become sensitive to the metabolic effects of insulin. A complex transcriptional cascade regulates this process, involving several distinct classes of transcription factor. In particular, the role of the nuclear hormone receptor PPARgamma will be discussed, along with bZip family members C/EBPalpha, C/EBPbeta, and C/EBPdelta. The relationship of adipose depots to the lymphatic system will also be discussed.
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PMID:The molecular control of adipogenesis, with special reference to lymphatic pathology. 1254 24

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

Peroxisome proliferator-activated receptor gamma (PPARgamma)-2 is a member of the nuclear hormone receptor superfamily that is expressed predominantly in adipocytes and is thought to have a role in energy homeostasis, adipogenesis, and insulin sensitivity. A functional single nucleotide polymorphism (SNP) that predicts a proline to alanine substitution (Pro12Ala) within the coding region of this gene has previously been associated with obesity and type 2 diabetes in several populations. In this study, we identified several novel SNPs in the promoter region of PPARgamma2 and genotyped them, along with the previously identified Pro12Ala SNP. In 241 nondiabetic Pima subjects, the Pro12Ala was associated with whole-body insulin action (P = 0.05), hepatic insulin action (P = 0.03), and fasting plasma insulin concentrations (P = 0.01). One of the promoter SNPs positioned within a putative E2 box was in high linkage disequilibrium (/D'/ = 0.98) with the Pro12Ala. This promoter SNP was similarly associated with whole-body insulin action (P = 0.04) and hepatic insulin action (P = 0.05), but not fasting plasma insulin concentrations. Functional studies in transfected 3T3-L1 cells demonstrated that this single base substitution in the putative E2 box significantly altered transcriptional activity from a luciferase reporter construct. These data indicate that this promoter SNP, via its effect on PPARgamma2 expression, may also have functional consequences on PPARgamma2-activated pathways, and perhaps both the promoter SNP and the Pro12Ala contribute to PPARgamma2-related phenotypes.
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PMID:A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. 1282 58

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important regulator of lipid and glucose homeostasis and cellular differentiation. Studies of many cell types in vitro and in vivo have demonstrated that activation of PPAR gamma can reduce cellular proliferation. We show here that activation of PPAR gamma is sufficient to reduce the proliferation of cultured insulinoma cell lines. We created a model with mice in which the expression of the PPARG gene in beta cells was eliminated (beta gamma KO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of beta-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in beta-cell mass, no effect on glucose homeostasis in beta gamma KO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and beta gamma KO mice revealed that PPAR gamma in beta cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPAR gamma function in beta-cell proliferation and also indicate that the mechanisms controlling beta-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
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PMID:Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. 1451 92

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.
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PMID:Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. 1550 33

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces beta-adrenergic receptor (beta-AR)-mediated adaptive thermogenesis. Beta-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30-60 min of beta-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase gamma3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and beta-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
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PMID:Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. 1564 Jan 43

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand--activated transcription factors. Three PPAR isoforms , designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention due to the key role these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation and blood pressure. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type II diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPARalpha activators such as fibric acid class of hypolipidemic drugs and PPARgamma agonists including antidiabetic thiazolidinediones (TZDs) have been proved to be effective for improving metabolic syndrome. All three PPAR isoforms appear to play important roles in the development of type II diabetes and diabetic nephropathy. Accumulating data has begun to emerge suggesting PPARs may serve as potential therapeutic targets for treating the metabolic syndrome and its related complications. Here we review the literature pertaining to the action, ligand selectivity and physiological role of PPARs. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of type II diabetes.
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PMID:[PPAR family and its relationship to metabolic syndrome]. 1588 36


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