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)

Hormone-sensitive lipase (HSL) plays an important role in energy metabolism by controlling the hydrolysis of triglycerides stored in adipose tissue. To investigate whether mutations in the HSL gene are associated with non-insulin-dependent diabetes mellitus (NIDDM), we screened for mutations of this gene using single-stranded conformation polymorphism (SSCP) in 35 Japanese subjects with NIDDM. SSCP analysis identified a variant pattern in axon 4, and the sequence showed that this variant pattern resulted from amino acid polymorphism (Arg309Cys). Subsequent study showed that this polymorphism was found in 18 of 151 NIDDM patients and 10 of 97 nondiabetic subjects, but allele frequency was not significantly different between the two groups (P = .7). Body mass index, serum triglyceride, and high-density lipoprotein (HDL) cholesterol were not different in subjects with and without the polymorphism. But serum total cholesterol was higher in subjects with the polymorphism than in subjects without it (P = .0005). These data indicate that this HSL polymorphism is not associated with NIDDM, obesity, and serum triglyceride level. However, an effect of the polymorphism to elevate serum total cholesterol has not been excluded, although further study is necessary to resolve its association with cholesterol metabolism.
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PMID:Detection of an amino acid polymorphism in hormone-sensitive lipase in Japanese subjects. 869 22

Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, we generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant HSL allele (HSL-/-) were superficially normal except that the males were sterile because of oligospermia. HSL-/- mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in HSL-/- mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in HSL-/- mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggests the heterogeneity of adipocytes. Despite these morphological changes, HSL-/- mice were neither obese nor cold sensitive. Furthermore, WAT from HSL-/- mice retained 40% of triacylglycerol lipase activities compared with the wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.
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PMID:Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. 1063 13

Hormone-sensitive lipase, the rate-limiting enzyme of intracellular TG hydrolysis, is a major determinant of fatty acid mobilization in adipose tissue as well as other tissues. It plays a pivotal role in lipid metabolism, overall energy homeostasis, and, presumably, cellular events involving fatty acid signaling. Detailed knowledge about its structure and regulation may provide information regarding the pathogenesis of such human diseases as obesity and diabetes and may generate concepts for new treatments of these diseases. The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general. A summary of the current knowledge regarding regulation of expression, potential involvement in lipid disorders, and role in tissues other than adipose tissue is also provided.
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PMID:Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. 1094 Mar 39

Studies have shown evidence of production of nitric oxide (NO) in adipose tissue, as well as inhibition of lipolysis by NO. We have analyzed nitric oxide synthase (NOS) expression in subcutaneous adipose tissue from 13 nonobese and 18 obese male subjects. Using a competitive reverse transcription polymerase chain reaction method, endothelial (eNOS) and inducible (iNOS), but not neuronal (nNOS), nitric oxide synthase mRNA expression was detected in isolated fat cells and pieces of adipose tissue. Tissue mRNA levels for eNOS were 3,814 +/- 825 and 5,956 +/- 476 amol/mg RNA (P = 0.043), and for iNOS 306 +/- 38 and 332 +/- 48 amol/mg RNA, for nonobese and obese individuals, respectively. Western blotting revealed similar eNOS protein levels in isolated fat cells and adipose tissue pieces. Protein levels for eNOS in nonobese and obese individuals, respectively, were (in optical density [OD] units per mm(2) per 100 microgram of total protein) 0.11 +/- 0.08 and 2.80 +/- 1.30 (P = 0.043). iNOS protein was detectable, but not measurable, at low levels in a subset of obese patients (3 of 10). iNOS protein levels could not be detected in nonobese individuals. Hormone-sensitive lipase (HSL), the key regulating enzyme in lipolysis, is reduced in obesity. The expression of HSL protein in subcutaneous adipose tissue was studied in the same subset of patients; in agreement with previous results, HSL levels were reduced in obese subjects: 4.64 +/- 1.10 and 1.27 +/- 0.35 (P = 0.012) in nonobese and obese subjects, respectively. In conclusion, this study shows that eNOS and iNOS, but not nNOS, are present in human subcutaneous adipose tissue. Gene expression and protein levels of eNOS are increased, whereas HSL protein levels are decreased in obesity. It is speculated that increased NO production, preferably by eNOS, and decreased HSL levels may cause decreased subcutaneous adipose tissue lipolysis in obesity. synthases in subcutaneous adipose tissue of nonobese and obese humans.
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PMID:Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans. 1094 12

Obesity is a disorder of energy balance. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol, the major form of stored energy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity. We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL. Plin -/- mice consume more food than control mice, but have normal body weight. They are much leaner and more muscular than controls, have 62% smaller white adipocytes, show elevated basal lipolysis that is resistant to beta-adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the Plin -/- alleles into Leprdb/db mice reverses the obesity by ncreasing the metabolic rate of the mice. Our results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.
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PMID:Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. 1110 49

Lipolysis in adipose tissue and balance between energy intake and expenditure are involved in the regulation of adipose tissue mass. Several recent findings suggest that alterations in the regulation of lipolysis and/or energy balance might contribute to the development of obesity. Hormone-sensitive lipase and uncoupling proteins play important role in regulation of lipolysis in adipose tissue as well as in the regulation of energy balance of various tissues. Mechanisms of the control of expression of genes coding synthesis of these proteins are poorly known. A brief overview of the present knowledge of the effects of nutritional intervention on the regulation of lipolysis in adipose tissue and on the expression of genes of hormone-sensitive lipase and that of uncoupling proteins is given in this article. Results of the authors' studies on the effect of calorie restriction on gene expression in adipose tissue are presented.
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PMID:[Effect of nutrition on adipose tissue metabolism in humans]. 1140 50

Hormone-sensitive lipase (HSL) is an intracellular neutral lipase that is capable of hydrolyzing triacylglycerols, diacylglycerols, monoacylglycerols, and cholesteryl esters, as well as other lipid and water soluble substrates. HSL activity is regulated post-translationally by phosphorylation and also by pretranslational mechanisms. The enzyme is highly expressed in adipose tissue and steroidogenic tissues, with lower amounts expressed in cardiac and skeletal muscle, macrophages, and islets. Studies of the structure of HSL have identified several amino acids and regions of the molecule that are critical for enzymatic activity and regulation of HSL. This has led to important insights into its function, including the interaction of HSL with other intracellular proteins, such as adipocyte lipid binding protein. Accumulating evidence has defined important functions for HSL in normal physiology, affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action; however, direct links between abnormal expression or genetic variations of HSL and human disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, await further clarification. The published reports examining the regulation, and function of HSL in normal physiology and disease are reviewed in this paper.
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PMID:Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. 1236 42

Hormone-sensitive lipase (HSL) catalyzes the intracellular hydrolysis of triacylglycerols and cholesteryl esters, and it is involved in regulating body fat, steroidogenesis, and insulin secretion. Thus, genetic variability at the HSL locus (LIPE) may play a significant role on lipid metabolism and the risk of obesity and type 2 diabetes. Therefore, we have examined two LIPE single nucleotide polymorphism (SNP) [14672C>G in the promoter region and 17948C>T (rs1206034) on intron 2] in relation to plasma lipids, anthropometrical and glucose-related phenotypes in a population of mostly overweight and obese men (373) and women (361). In women, the 17948T allele was associated with decreased total cholesterol (TC, p = 0.001), LDL-cholesterol (LDLc, p < 0.001) and apoE concentrations (p = 0.041). Conversely, female carriers of the LIPE 14672G allele had significantly higher TC (p = 0.047), LDLc (p = 0.041), and apoE (p = 0.041) levels. Although we did not find significant associations in men, we observed that male carriers of the LIPE 14672G who did not drink alcohol showed higher glucose levels than non-carriers (p = 0.008), whereas there were no allele-related differences among drinkers (p = 0.019 for the interaction). These SNPs were not significantly associated with anthropometrical variables. In summary, variation at this locus showed gender-specific associations with lipids and glucose measures, and the latter was influenced by alcohol drinking.
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PMID:Genetic variation at the hormone sensitive lipase: gender-specific association with plasma lipid and glucose concentrations. 1498 67

Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50-80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.
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PMID:Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. 1570 80

Adipose tissue lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and release of fatty acids and glycerol. Recent work has revealed that lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. There have been new discoveries on the endocrine and paracrine regulation of lipolysis and on the molecular mechanisms of triglyceride hydrolysis. Catecholamines modulate lipolysis through lipolytic beta-adrenoceptor and antilipolytic alpha2-adrenoceptor. Recent studies have allowed a better understanding of the relative contribution of the two types of receptors and provided evidence for the in vivo involvement of alpha2-adrenoceptors in the physiological control of subcutaneous adipose tissue lipolysis. A puzzling observation is the characterization of a residual catecholamine-induced lipolysis in mice deficient in beta-adrenoceptors. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. There are other lipolytic pathways active in human fat cells which importance is not fully understood. Forty years after the description of the antilipolytic effect of nicotinic acid, the receptors have been identified. Adrenomedullin which is produced by adipocytes exert an antilipolytic effect through an indirect mechanism involving nitric oxide. The molecular details of the lipolytic reaction are not fully understood. The role of the lipases has been re-evaluated with the cloning of adipose triglyceride lipase. Hormone-sensitive lipase appears as the major lipase for catecholamine and natriuretic peptide-stimulated lipolysis whereas adipose triglyceride lipase mediates the hydrolysis of triglycerides during basal lipolysis. Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation. Re-organization of the lipid droplet coating by perilipins facilitates the access of the enzyme. The role of other lipid-interacting proteins in lipolysis is still unclear. The proteins involved in the lipolytic process constitute drug targets for the treatment of obesity and the metabolic syndrome. The oldest example is nicotinic acid (niacin) used as a hypolipidaemic drug. A first approach consists in molecules stimulating lipolysis and oxidation of the released fatty acids to decrease fat stores. A second approach is a chronic inhibition of lipolysis to diminish plasma fatty acid level which is a central feature of the metabolic syndrome.
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PMID:Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. 1664 34


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