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

Lipodystrophy is a common alteration in HIV 1-infected patients under anti-retroviral treatment. This syndrome is usually associated with peripheral lipoatrophy, central adiposity and, in some cases, lipomatosis, as well as systemic insulin resistance and hyperlipidemia. Research on the ethiopathogenesis of the disease revealed novel aspects of adipose tissue biology highly relevant to obesity research: the pivotal role of mitochondria in white adipose tissue function, the role that interference with master transcription factors of adipogenesis may have in human adipose tissue, the capacity of human white adipose tissue to acquire brown fat-like features, as well as the importance of apoptosis and the potential impact of viral infections in adipose tissue. The dramatic difference between subcutaneous adipose depots, prone to lipoatrophy, and the visceral adipose depots, prone to enlargement, has been further evidenced in the study of the lipodystrophy syndrome. The recognition of a local pro-inflammatory environment in lipoatrophic adipose tissue from affected patients, including macrophage infiltration and enhanced expression of chemokines and cytokines, points to events paradoxically similar to those in the hypertrophied adipose tissue in obesity. However, this also potentially provides an explanation for the existence of systemic alterations common to lipodystrophy and obese patients and reminiscent of the metabolic syndrome.
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PMID:Lipodystrophy in HIV 1-infected patients: lessons for obesity research. 1765 62

The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities.
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PMID:PCK1 and PCK2 as candidate diabetes and obesity genes. 1770 78

Long considered scarcely more than an uninteresting energy depot, adipose tissue has recently achieved star status. Far from being mere fat droplets, the adipocytes secrete a number of hormones and bioactive peptides, collectively known as adipokines, which participate in the regulation of a variety of functions, from haemostasis to angiogenesis to energy balance. Adipose tissue constitutes a bona-fide endocrine organ whose main dysfunctions, obesity and lipodystrophy, are related to the development of diabetes, hypertension, or dyslipidemia. The renewed interest in this tissue has prompted an escalation in the number of studies focusing on every aspect of the biology of the adipose cell, in the belief that a detailed knowledge of the mechanisms involved in the differentiation and function of adipocytes may contribute new therapeutical approaches to the treatment of such alarming medical problems. Adipogenesis is the result of an intertwined network of transcription factors and coregulators with chromatin-modifying activities that together, are responsible for the establishment of the gene expression pattern of mature adipocytes. Although the exquisitely regulated transcription factor cascade controlling adipogenesis has been extensively studied, the role of chromatin and chromatin-modifying proteins has become apparent only in recent times.
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PMID:Chromatin and chromatin-modifying proteins in adipogenesis. 1771 75

The metabolic syndrome refers to insulin resistance and its associated cluster of related cardiovascular metabolic risk factors including type 2 diabetes, hypertension, dyslipidemia and central obesity. Although many hypotheses and facts have been proposed to explain the interaction between genetic and environmental causes of this syndrome, the primary etiology of the metabolic syndrome is adipose tissue dysregulation. Firstly, the thrifty genotype and phenotype hypothesis may explain the endemic increase in type 2 diabetes and cardiovascular disease in developing countries and elucidates the congenital susceptibility and environmental triggering of the metabolic syndrome. Secondly, over-nutrition leads to fatty acid (FA) accumulation in adipocytes and to an overflow to ectopic fat storage organs. This causes functional changes in adipocytes shifting the intra-cellular metabolic pathway toward insulin resistance. Thirdly, obese subjects exhibit increased fat cell size and over-secretion of biologic adipocytokines. Fourthly, failure to adequately develop adipose tissue mass, as seen in lipodystrophy cases, causes severe insulin resistance and diabetes. Lastly, similar to human type 2 diabetes, Psammonys obesus, a desert rat which feeds mainly on low-calorie vegetation, develops the metabolic syndrome when given a diet of calorie rich food. The above evidence indicates adipocyte dysregulation and secretion of FA as well as certain molecules from overloaded adipocytes/adipokines contribute to the pathogenesis of impaired insulin secretion and insulin resistance, endothelial dysfunction, a pro-inflammatory state and promote progression of atherosclerosis. The metabolic syndrome is a modern disease resulting adipocyte dysmetabolism resulting from the paradox of the slow human evolution combined with rapid environmental changes.
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PMID:Congenital and environmental factors associated with adipocyte dysregulation as defects of insulin resistance. 1782 91

The zinc-finger transcription factor SLUG (SNAI2) triggers epithelial-mesenchymal transitions (EMTs) and plays an important role in the developmental processes. Here, we show that SLUG is expressed in white adipose tissue (WAT) in humans and its expression is tightly controlled during adipocyte differentiation. Slug-deficient mice exhibit a marked deficiency in WAT size, and Slug-overexpressing mice (Combi-Slug) exhibit an increase in the WAT size. Consistent with in vivo data, Slug-deficient mouse embryonic fibroblasts (MEFs) showed a dramatically reduced capacity for adipogenesis in vitro and there was extensive lipid accumulation in Combi-Slug MEFs. The analysis of adipogenic gene expression both in vivo and in vitro showed that peroxisome proliferator-activated factor gamma2 (PPARgamma2) expression was altered. Complementation studies rescued this phenotype, indicating that WAT alterations induced by Slug are reversible. Our results further show a differential histone deacetylase recruitment to the PPARgamma2 promoter in a tissue- and Slug-dependent manner. Our results connect, for the first time, adipogenesis with the requirement of a critical level of an EMT regulator in mammals. This work may lead to the development of targeted drugs for the treatment of patients with obesity and/or lipodystrophy.
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PMID:Adipose tissue mass is modulated by SLUG (SNAI2). 1790 53

The aim of this study was to analyze LPIN1 adipose tissue gene expression levels in 3 clinical insulin-resistant conditions-obesity, type 2 diabetes mellitus, and human immunodeficiency virus (HIV)-associated lipodystrophy-and its relationship with adipogenic and inflammatory markers. Subcutaneous adipose tissue samples were obtained from 2 cohorts: 98 subjects with different degrees of adiposity and with or without the presence of type 2 diabetes mellitus and 37 HIV-infected patients. Real-time polymerase chain reaction was used to measure gene expression of LPIN1 and adipogenic (PPARgamma, SREBP1c) and inflammatory markers (IL6, TNFalpha, TNFR1, and TNFR2). LPIN1 messenger RNA expression levels were significantly lower in the obese group (P = .002), were similar in type 2 diabetes mellitus patients and control subjects (P = .211), and were significantly higher in HIV-infected patients (P < .001). LPIN1 messenger RNA levels positively correlated with insulin sensitivity in all subjects. Moreover, an inverse correlation with proinflammatory cytokines was observed.
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PMID:Human subcutaneous adipose tissue LPIN1 expression in obesity, type 2 diabetes mellitus, and human immunodeficiency virus--associated lipodystrophy syndrome. 1795 Jan 3

The use of highly active antiretroviral therapy (HAART) in HIV-1 infection confers immunological and survival advantages, at the cost of induction of significant metabolic disturbances. These include insulin resistance, disturbances in lipid metabolism, glucose homeostasis, adipocyte physiology and body fat partitioning with peripheral lipoatrophy and visceral obesity. These metabolic disturbances produce clinical manifestations which impact on the future health of the HIV-infected patient, including hyperlipidaemia, lipodystrophy, metabolic syndrome, cardiovascular disease and type 2 diabetes. These conditions are evident in the relative short term as HAART (and possibly HIV infection) appears to accelerate their pathogenesis. The current understanding of the mechanisms and time courses for developing metabolic complications on HAART is reviewed in this paper. The efficacy of therapeutic interventions for insulin resistance, hyperlipidaemia, body fat partitioning disorders and metabolic syndrome is summarized.
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PMID:Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection. 1807 Aug 30

Both the disproportionate loss of adipose tissue in the case of lipodystrophies and the disproportionate gain of adipose tissue in obesity are frequently associated with an increase in insulin resistance and its complications. Leptin replacement is a very promising therapeutic approach for the management of the complications of lipodystrophy. In contrast, leptin treatment for the reversal of obesity-related metabolic disorders has not proven to be successful. There is a need to better understand both of these phenomena. Mouse models of lipodystrophy may provide us with new pharmaceutical targets for the treatment and prevention of metabolic disturbances related to dysfunctional adipose tissue both in the context of lipodystrophy and obesity.
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PMID:Mouse Models of Lipodystrophy Key reagents for the understanding of the metabolic syndrome. 1819 96

Adipose tissue is unique in that it can undergo significant hypertrophy and atrophy, resulting in wide ranges of obesities and lipodystrophies. At the base of this elasticity is the lipid-filled adipocyte, which can either overfill by storing large amounts of triglycerides or shrink to a tiny cell by depleting its lipids and as such is remarkable in sustaining insults. As a major energy reservoir, the adipocyte may hold considerable calories necessary for survival and reproduction, two functions that are essential for the survival of the species. This review will summarize some of the recent studies that have advanced our understanding of the central and peripheral mechanisms that are initiated by adipocyte-secreted factors such as leptin, adiponectin, resistin, and retinol-binding protein 4. The intersection of obesity and lipodystrophy results in insulin resistance, which may be unlocked by elucidating the roles of these factors in pathways that control insulin sensitivity and glucose uptake.
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PMID:Obesity and lipodystrophy--where do the circles intersect? 1820 37

In conditions such as obesity and lipodystrophy, insulin resistance and diabetes are associated with the dysregulation of lipid metabolism in adipose tissue, skeletal muscle and liver. One factor that influences lipid homeostasis in all three of these tissues is lipin 1. Studies in mouse models and humans have established a relationship between lipin 1 levels and both triglyceride storage in adipose tissue and insulin sensitivity. Thus, lipin 1 deficiency in the mouse results in lipodystrophy and insulin resistance. In contrast, fat-specific expression of a lipin 1 transgene results in increased triglyceride storage in adipose tissue and insulin sensitivity, despite the development of obesity. In humans, lipin 1 expression levels in adipose tissue are positively correlated with insulin sensitivity, and inversely correlated with inflammatory cytokine expression and intramyocellular lipid, a key marker of insulin resistance. These data from mouse and human studies suggest a role for lipin 1 in directing lipid to the appropriate storage site in adipose tissue, thus potentially reducing lipid accumulation in tissues such as muscle and liver. The mechanism of lipin 1 action appears to be complex, with evidence for roles in triglyceride biosynthesis and in the regulation of gene expression.
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PMID:The role of lipin 1 in adipogenesis and lipid metabolism. 1826 74


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