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)

Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.
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PMID:Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. 1134 6

Lipodystrophy is one of the most common and distressing side effects associated with combination therapy. Some aspects of the phenomenon were reported several years ago, but the frequency of reports has greatly increased with the introduction of protease inhibitors in 1996. Lipodystrophy is a redistribution of fat, and the cause of the change is uncertain. It is not known if it is a signal of disease progression, or a result of anti-HIV therapy. A report on three separate cases conveys success in treating lipodystrophy associated with the use of protease inhibitors. All cases switched people from protease inhibitors to non-nucleoside reverse transcriptase inhibitors (NNRTI), however 10 percent of the group had increases in HIV levels. Serostim, a human growth hormone, has also had some effect in reducing central obesity and buffalo hump, but does not seem to be effective on facial and limb wasting or on decreasing lipid levels. To date, most studies on lipodystropy have been driven by AIDS activists, with pharmaceutical companies and the research community being slow to follow. There is very little information on treating this syndrome, and it is unclear how widespread its effects are. Reports on incidence levels range from 15 percent to 75 percent.
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PMID:Lipodystrophy. 1136 31

Recent studies in murine models suggest that resistin (also called Fizz3 [1]), a novel cysteine-rich protein secreted by adipocytes, may represent the long-sought link between obesity and insulin resistance (2). Furthermore, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists appear to inhibit resistin expression in murine adipocytes, providing a possible explanation for the mode of action of this class of insulin sensitizers (2). Using a fluorescent real-time reverse transcriptase-polymerase chain reaction-based assay, we found that resistin mRNA levels in whole adipose tissue samples were increased in morbidly obese humans compared with lean control subjects. However, in freshly isolated human adipocytes, resistin mRNA levels were very low and showed no correlation with BMI. Resistin mRNA was undetectable in preadipocytes, endothelial cells, and vascular smooth muscle cells, but it was readily detectable in circulating mononuclear cells. Although exposure of human mononuclear cells to PPAR-gamma agonists markedly upregulated fatty acid-binding protein-4 expression, these agents had no effect on mononuclear cell resistin expression. Finally, resistin mRNA was undetectable in adipocytes from a severely insulin-resistant subject with a dominant-negative mutation in PPAR-gamma (3). We conclude that the recently described relationships of murine resistin/Fizz3 expression with obesity, insulin resistance, and PPAR-gamma action may not readily translate to humans. Further studies of this novel class of proteins are needed to clarify their roles in human metabolism.
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PMID:Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. 1157 98

Lactic acidosis has been reported as a rare but potentially fatal complication of anti-retroviral therapy in HIV-infected patients, mostly with nucleoside analogues. Two cases of lactic acidosis with a favorable prognosis are here reported. So far, no distinct risk factors associated with the development of lactic acidosis have been identified which were associated with the use of anti-retroviral agents, apart from female sex, obesity, and the prolonged use of necleoside reverse transcriptase inhibitors. Currently, there is no specific treatment for this condition, apart from drug discontinuation and hydro-electrolytic support. Several therapies based upon the pathophysiology of this entity have been tested, but none of them has been validated so far.
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PMID:[Symptomatic hyperlactatemia associated with the use of antiretroviral agents]. 1236 52

Changes in body fat in persons infected with the human immunodeficiency virus (HIV) have been associated with deleterious changes in blood lipids and insulin resistance, raising concern that these changes will increase the risk for accelerated atherosclerosis. Changes in body fat are often identified in advanced disease but may also occur early after HIV infection is detected. Conflicting evidence suggests that fat maldistribution may be related to use of protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or a combination of these two classes of drugs, but the etiologies of the various changes in body fat remain uncertain. To date there have been no remedies for the loss of subcutaneous fat, but recent evidence has suggested that discontinuation of stavudine or zidovudine therapy may be associated with limited restoration of extremity fat. For fat accumulation, a number of strategies have been attempted, including treatment with human growth hormone, androgens, or metformin, and changes in diet and exercise. As in persons not infected with HIV, it is expected that the cornerstone of management, especially in the presence of central obesity, dyslipidemia, and insulin resistance, will include a diet low in saturated fat, with low-glycemic index carbohydrates, and high in fiber. Very limited evidence in persons infected with HIV has suggested that a supervised exercise program may be beneficial.
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PMID:Body habitus changes related to lipodystrophy. 1265 76

Three new spontaneous recessive mouse mutations in the leptin receptor gene (Lepr), Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy), originated in the CBA/J (CBA), B10.D2-H8(b)(57N)/Sn (B10) and NU/J strains, respectively. Lepr(db-rtnd) and Lepr(db-dmpg) were maintained on C57BL/6J (B6), resulting in congenic lines of B6.CBA-Lepr(db-rtnd) and B6.B10-Lepr(db-dmpg). Lepr(db-rtnd) was also maintained on CBA post F1 generation of a cross between the B6 and the CBA, generating the congenic line CBA.B6CBA-Lepr(db-rtnd). Lepr(db-rlpy) was maintained as a coisogenic strain. The aims of this study were to determine the molecular bases for these new Lepr mutations and to characterize the new mutant stocks, with respect to obesity and diabetes. Mutations were analyzed by Southern blot analysis, reverse transcriptase-polymerase chain reaction and sequencing. Body weights and plasma glucose and insulin levels were measured, and the histology of the pancreas was carried out. Lepr(db-rtnd) contained one G deletion in exon 4 of Lepr, introducing a frameshift and premature termination. Lepr(db-dmpg) had a deletion in the extracellular domain of LEPR: Lepr(db-rlpy) exhibited a large DNA deletion, leading to a complete lack of LEPR: All three mutations led to morbid obesity and diabetes. It is noteworthy that Lepr(db-rtnd) caused milder hyperglycemia accompanied by higher plasma and pancreatic insulin contents on B6 compared to that on CBA backgrounds. In summary, we discovered three new mutations of Lepr, providing new mouse models for obesity and diabetes. Furthermore, our mutant stocks will be useful in elucidating the effects of the genetic background on the Lepr mutations and in testing the specificity of antibodies to LEPR.
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PMID:New leptin receptor mutations in mice: Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy). 1273 Apr 8

Starting from the very simple molecule sulfamic acid, O-substituted-, N-substituted-, or di-/tri-substituted sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents, which are on one hand due to the relative ease with which such compounds are synthesized, and on the other one, due to the fact that biological activity of most of them is impressive.
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PMID:Sulfamates and their therapeutic potential. 1547 25

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis. SAA3 mRNA was dramatically induced up to 77-fold during differentiation of 3T3-L1 preadipocytes. Furthermore, 100 nM dexamethasone and 30 ng/ml interleukin (IL)-6 induced SAA3 mRNA by up to 11- and 4.8-fold, respectively, in a time-dependent fashion with significant stimulation observed at concentrations as low as 10 nM dexamethasone and 1 ng/ml IL-6. In contrast, insulin, isoproterenol and growth hormone did not influence SAA3 synthesis. Inhibitor studies suggested that the positive effect of IL-6 on SAA3 expression is at least in part mediated by Janus kinase 2. Taken together, our results show a differential regulation of SAA3 by glucocorticoids and IL-6 supporting an integrative role of this acute-phase reactant in the pathogenesis of insulin resistance and its link to obesity and cardiovascular disease.
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PMID:Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. 1559 Sep 82

A better understanding of the mechanism of adipose tissue differentiation is of paramount importance in the development of therapeutic strategies for the treatment and prevention of obesity and type 2 diabetes mellitus. Optimal results using tissue culture models can be expected only when the in vitro adipocyte resembles adipose tissue in vivo as closely as possible. In this study, we used tissue-engineering principles to develop a three-dimensional (3-D) culture system to mimic the geometry of adipose tissue in vivo. Mouse preadipocyte 3T3-L1 cells were seeded onto nonbiodegradable fibrous polyethylene terephthalate scaffolds and differentiated with a hormone cocktail consisting of insulin, dexamethasone, isobutylmethylxanthine, and fetal calf serum. Cell morphology, growth, differentiation, and function were studied by immunocytochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay, and oil red O staining. Cells grown on 3-D fibrous scaffolds were differentiated in situ by hormone induction with high efficiency (approximately 90%) as shown by scanning electron microscopy. Immunocytochemistry, immunoblot analysis, and RT-PCR revealed that the 3-D constructs expressed adipocyte-specific genes, including peroxisome proliferator-activated receptor gamma, leptin, adipsin, aP2, adiponectin, GLUT4, and resistin. Adipocytes matured on 3-D constructs secreted leptin at levels even greater than that of fully differentiated adipocytes in 2-D conventional cell cultures. Finally, adipocyte-specific phenotypic function was demonstrated by accumulation of neutral lipids in larger fat droplets. In conclusion, preadipocytes grown on 3-D matrices acquire morphology and biological features of mature adipocytes. This new culture model should have significant utility for in vitro studies of adipocyte cell biology and development.
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PMID:Adipose tissue model using three-dimensional cultivation of preadipocytes seeded onto fibrous polymer scaffolds. 1586 24

Obesity is associated with elevated levels of leptin in the blood. Elevated leptin is a risk factor for thrombosis in humans, and leptin administration promotes platelet activation and thrombosis in the mouse. The current study examines the effect of leptin on human platelets, and provides initial insights into the nature of the leptin receptor on these platelets. Leptin potentiated the aggregation of human platelets induced by low concentrations of ADP, collagen and epinephrine. However, the response varied significantly between donors, with platelets from some donors (approximately 40%) consistently responding to leptin (responders) and those from other donors (approximately 60%) never responding (non-responders). Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) experiments showed that platelets from both groups only express the signaling form of the leptin receptor, and that responder platelets express higher levels of this receptor than non-responders. Ligand-binding assays demonstrate specific, saturable binding of leptin to platelets from both groups with apparent K(d) values of 76 +/- 20 nM for responders and 158 +/- 46 nM for non-responders. Thus, the decreased sensitivity of non-responder platelets to leptin does not result from the absence of the signaling form of this receptor, but may reflect differences in its level of expression and/or affinity for leptin. These preliminary studies demonstrate that platelets are a major source of leptin receptor in the circulation, and suggest that leptin-responsive individuals may have a higher risk for obesity-associated thrombosis than non-responsive individuals.
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PMID:The leptin receptor system of human platelets. 1586 2


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