Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth differentiation factor 3 (GDF-3) is structurally a bone morphogenetic protein/growth differentiation factor subfamily member of the TGF-beta superfamily. GDF-3 exhibits highest level of expression in white fat tissue in mice and is greatly induced by high fat diet if fat metabolic pathway is blocked. To identify its biological function, GDF-3 was overexpressed in mice by adenovirus mediated gene transfer. Mice transduced with GDF-3 displayed profound weight gain when fed with high fat diet. The phenotypes included greatly expanded adipose tissue mass, increased body adiposity, highly hypertrophic adipocytes, hepatic steatosis, and elevated plasma leptin. GDF-3 stimulated peroxisome proliferator activated receptor expression in adipocytes, a master nuclear receptor that controls adipogenesis. However, GDF-3 was not involved in blood glucose homeostasis or insulin resistance, a condition associated with obesity. In contrast, similar phenotypes were not observed in GDF-3 mice fed with normal chow, indicating that GDF-3 is only active under high lipid load. Thus, GDF-3 is a new non-diabetic adipogenic factor tightly coupled with fat metabolism.
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PMID:GDF-3 is an adipogenic cytokine under high fat dietary condition. 1535 31

Transforming growth factor beta-1 is involved in local signaling for a variety of human diseases including renal diseases, cardiac hypertrophy and fibrosis in heart failure, hepatic fibrosis, and pulmonary fibrosis. Elevated levels of circulating transforming growth factor beta-1 result in organ fibrosis in animal models. In humans smoking, hypertension, diabetes and obesity appear to result in elevated circulating levels. This paper outlines a hypothesis that elevated circulating levels of transforming growth factor beta-1 are part of the molecular link between several entities that have epidemiologic ties including hypertension, diabetes, smoking and obesity on one hand and diseases resulting in organ fibrosis on the other including renal disease and cardiac fibrosis and hypertrophy in heart failure. Additionally, it is suggested that elevated levels are not simply a marker of a similar mechanism of disease production but that elevated levels of circulating transforming growth factor beta-1 lead to disease production and to the synergy of risk factors seen in production of human fibrotic diseases.
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PMID:Circulating transforming growth factor beta-1: a partial molecular explanation for associations between hypertension, diabetes, obesity, smoking and human disease involving fibrosis. 1612 68

Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the role of leptin in fibrogenesis in the liver. Xenobiotics-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, an inborn leptin- and leptin receptor (Ob-R)-deficient animal, respectively. Further, leptin increased transforming growth factor (TGF)-beta mRNA in isolated sinusoidal endothelial cells and Kupffer cells, suggesting that leptin promotes hepatic fibrogenesis through up-regulation of TGF-beta in the liver. Moreover, leptin augmented PDGF-dependent proliferation of HSCs by enhancing downstream intracellular signaling pathways via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/Akt. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. These findings indicate that leptin is one of the key regulators for inflammation and progression of fibrosis in various chronic liver diseases including NASH.
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PMID:The role of leptin in progression of non-alcoholic fatty liver disease. 1619 23

Insulin resistance has been implicated as one possible factor that links visceral obesity to unfavourable metabolic and cardiovascular consequences. However, the mechanism whereby adipose tissue causes alterations in insulin action remains unclear. White adipose tissue is secreting several hormones, particularly leptin and adiponectin, and a variety of other protein signals: the adipocytokines. They include proteins involved in the regulation of energy balance, lipid and glucose metabolism as well as angiogenesis, vascular and blood pressure regulation. Visceral obesity and inflammation within white adipose tissue may be a crucial step contributing to the emergence of insulin resistance, type 2 diabetes and atherosclerosis. A growing list of adipocytokines involved in inflammation (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, TGF-beta,) and the acute-phase response (serum amyloid A, PAI-1) have been found to be increased in the metabolic syndrome. It is, however, unclear as to the extent adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and how they may affect the insulin-dependent tissues. This review describes the role of the currently known adipocytokines and hormones released by adipose tissue in generating the insulin resistance state and the chronic inflammatory profile which frequently goes together with visceral obesity.
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PMID:Review article: adipocytokines and insulin resistance. 1622 63

Calorie-enriched diet and lack of exercise are causing a worldwide surge of obesity, insulin resistance and lipid accretion in liver (i.e. hepatic steatosis), which can lead to steatohepatitis. Steatosis and nonalcoholic steatohepatitis (NASH) can also be induced by drugs such as amiodarone, tamoxifen and some antiretroviral drugs, including stavudine and zidovudine. There is accumulating evidence that mitochondrial dysfunction (more particularly respiratory chain deficiency) plays a key role in the physiopathology of NASH whatever its initial cause. In contrast, the mitochondrial beta-oxidation of fatty acids can be either increased (as in insulin resistance-associated NASH) or decreased (as in drug-induced NASH). However, in both circumstances, generation of reactive oxygen species (ROS) by the damaged respiratory chain can be augmented. ROS generation in an environment enriched in lipids in turn induces lipid peroxidation which releases highly reactive aldehydic derivatives (e.g. malondialdehyde) that have diverse detrimental effects on hepatocytes and other hepatic cells. In hepatocytes, ROS, reactive nitrogen species and lipid peroxidation products further impair the respiratory chain, either directly or indirectly through oxidative damage to the mitochondrial genome. This consequently leads to the generation of more ROS and a vicious cycle occurs. Mitochondrial dysfunction can also lead to apoptosis or necrosis depending on the energy status of the cell. ROS and lipid peroxidation products also increase the generation of several cytokines (TNF-alpha, TGF-beta, Fas ligand) playing a key role in cell death, inflammation and fibrosis. Recent investigations have shown that some genetic polymorphisms can significantly increase the risk of steatohepatitis and that several drugs can prevent or even reverse NASH. Interestingly, most of these drugs could exert their beneficial effects by improving directly or indirectly mitochondrial function in liver. Finding a drug, which could fully prevent oxidative stress and mitochondrial dysfunction in NASH is a major challenge for the next decade.
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PMID:Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. 1640 28

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.
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PMID:Obese state leads to elevated levels of TGF-beta and COX isoforms in platelets of Zucker rats. 1647 87

Obesity is one of the most frequently encountered medical problems of our time. Among the complications of this pathologic entity, renal disease is an important issue and its pathophysiologic mechanisms are a challenge for the physician, since a variety of etiologic factors are implicated in its genesis. For example, hypertension, hyperlipidemia and insulin resistance affect renal function, each one in a different way. Obesity seems to be a state in which kidneys demonstrate morphological and functional alterations, while hormonal and growth factors play a significant role. Among them, leptin, a recently discovered cytokine, has undergone extended investigation and has proven to be a factor that contributes to renal disease, mainly through mechanisms that involve activation of the TGF-beta system resulting in glomerulopathy and related clinical symptoms. Experiments in animals have revealed interesting aspects as far as the role of leptin in kidney function. Understanding the underlying mechanisms of obesity-related glomerulopathy may become a valuable aid in handling an obese patient with renal disease and associated problems.
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PMID:Obesity and renal disease: a possible role of leptin. 1661 10

Leptin is a peptide hormone that is mainly, but not exclusively, produced in adipose tissue and plays a pivotal role in regulating food intake and energy expenditure. Besides its effects on regulation of body weight, appetite and energy expenditure, leptin exhibits influence on the immune system and may contribute to the deterioration of renal function. These direct and indirect renal effects of leptin could partly explain obesity-associated kidney disease and may be also relevant for diabetic nephropathy in type 2 diabetes. Leptin is primarily metabolized in the kidney, presumably by binding to megalin, a multiligand receptor in the proximal tubule, tubular uptake and endocytosis. The kidney expresses abundant concentrations of the small isoform of the leptin receptor (Ob-Ra). In cultured renal rat endothelial cells and mesangial cells obtained from db/db mice, leptin can signal through the Ob-Ra receptor isoform. The peptide stimulates proliferation of glomerular endothelial cells, increases TGF-beta1 synthesis, and collagen type IV production. In contrast, leptin did not influence TGF-beta1 production in mesangial cells, but the peptide stimulates glucose transport in these cells, increased collagen type I synthesis, and lead to an upregulation of surface TGF-beta type II receptors through signal transduction pathways involving phosphatidylinositol-3-kinase. Leptin also stimulates hypertrophy, but not proliferation in cultured rat mesangial cells. Infusion of leptin for 3 weeks into normal rats fosters development of glomerulosclerosis and proteinuria. In addition, transgenic mice with leptin overexpression demonstrated a increase in collagen type IV and fibronectin mRNA in the kidney. Additional previously described direct and indirect effects of leptin on the kidney include natriuretic effects, an increase in sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is a target organ for leptin and that this hormone might play an important role in renal pathophysiology.
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PMID:Leptin and renal fibrosis. 1692 41

A pluripotent cell line, C3H10T1/2, is induced to undergo adipogenesis by a mixture of factors that includes a glucocorticoid such as dexamethasone. We found that expression of myostatin (MSTN), a TGF-beta family member extensively studied in muscle, was induced by dexamethasone under those differentiation conditions. Moreover, MSTN could substitute for dexamethasone in the adipogenesis mixture. However, the adipocytes induced by MSTN in both cell culture and transgenic mice were small and expressed markers characteristic of immature adipocytes. These adipocytes exhibited cell-autonomous increases in insulin sensitivity and glucose oxidation. In mice, these effects produced elevated systemic insulin sensitivity and resistance to diet-induced obesity. Modulation of the final stages of adipogenesis may provide a novel approach to understanding and treating metabolic disease.
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PMID:Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. 1703 Aug 20

There is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular and at the cytokine expression levels. Our in vivo results confirm the immune deficiency of ob/ob mice, leptin deficient and massively obese, characterized by a reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved in T lymphocyte priming, are affected in obese mice. Both their function and their steady-state number are disturbed. We demonstrate that DCs from ob/ob mice are less potent in stimulation of allogenic T cells in vitro. This impaired functionality is not associated with altered expression of phenotypic markers but with the secretion of immunosuppressive cytokines such as TGF-beta. Moreover, we show increased in vivo steady-state number of epidermal DCs in ob/ob mice, which is not due to a migratory defect. The ob/ob mice are characterized by the absence of functional leptin, a key adipokine linking nutrition, metabolism, and immune functions. Interestingly, intradermal injection of leptin is able to restore epidermal DC number in obese mice. Thus, DCs might be directly sensitive to metabolic disturbances, providing a partial explanation of the immunodeficiency associated with obesity.
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PMID:Impairment of dendritic cell functionality and steady-state number in obese mice. 1705 24


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