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

Published studies have shown that overproduction of very low density lipoproteins is a major factor leading to hypertiglyceridemia in obesity. Few systematic studies of triglyceride removal or postheparin lipoprotein lipase activity (LPLA) in obesity have appeared. We have examined heparin-released lipoprotein triglyceride hydrolase activities in 12 lean and 12 obese age- and sex-matched volunteers after overnight fasting. Heparin doses were calculated to compensate for the disproportionality between body mass and plasma volume in obesity. Triglyceride hydrolase activities of hepatic (HTGLA) and extrahepatic (LPLA) origin were distinguished by in vitro inhibition of LPLA with protamine sulfate. Incremental heparin doses were given to each subject to determine lipase activities under conditions of maximal release and to define sensitivity to heparin-facilitated lipase release. Maximal postheparin LPLA and HTGLA (u/ml plasma or u/total plasma vol) were similar in lean and obese individuals despite a nearly three-fold increase in calculated adipose tissue mass in the obese. Since adipose tissue LPLA has been reported to increase in proportion to adipocyte size, the lack of difference in maximal postheparin LPLA was expected. There was an inverse correlation between plasma triglyceride concentration and LPLA/kg adipose tissue. These empirical observations may reflect relatively decreased heparin-releaseable (functional) LPLA in relation to adipose organ mass in obese subjects. The mechanism of this relationship has not been established.
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PMID:Postheparin plasma lipase activities in obesity: failure to increase with adipose organ enlargement. 68 71

We have used rat cDNA microarrays to identify adipocyte-specific genes that could play an important role in adipocyte differentiation or function. Here, we report the cloning and identification of a 2.0-kb mRNA coding for a putative protein that we have designated as desnutrin. The novel gene is expressed predominantly in adipose tissue, and its expression is induced early during 3T3-L1 adipocyte differentiation. Desnutrin mRNA levels were regulated by the nutritional status of animals, being transiently induced during fasting. In vitro desnutrin gene expression was up-regulated by dexamethasone in a dose-dependent manner but not by cAMP, suggesting that glucocorticoids could mediate the increase in desnutrin mRNA levels observed during fasting. Desnutrin mRNA codes for a 486-amino acid putative protein containing a patatin-like domain, characteristic of many plant acyl hydrolases belonging to the patatin family. Confocal microscopy of enhanced green fluorescent protein-tagged desnutrin protein-transfected cells showed that the fusion protein localized in the cytoplasm. Moreover, cells overexpressing desnutrin by transfection showed an increase in triglyceride hydrolysis. Interestingly, we also found that the desnutrin gene expression level was lower in ob/ob and db/db obese mouse models. Overall, our data suggest that the newly identified desnutrin gene codes for an adipocyte protein that may function as a lipase and play a role in the adaptive response to a low energy state, such as fasting, by providing fatty acids to other tissues for oxidation. In addition, decreased expression of desnutrin in obesity models suggests its possible contribution to the pathophysiology of obesity.
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PMID:Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. 1533 59

Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals.
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PMID:Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. 1555 Jun 74

Recently, adipose triglyceride lipase (ATGL, also called desnutrin and calcium-independent phospholipase A2 [iPLA(2)] zeta) was isolated as a novel adipose-expressed triglyceride lipase which is downregulated in obesity and may contribute to obesity-associated metabolic disorders such as hyperlipidemia and insulin resistance. To clarify expression and regulation of this fat-derived lipase, ATGL mRNA was measured in 3T3-L1 adipocytes by quantitative real-time reverse transcription-polymerase chain reaction after treatment with isoproterenol, tumor necrosis factor (TNF) alpha, insulin, and growth hormone (GH) which have been shown to influence lipolysis and insulin sensitivity profoundly. Interestingly, treatment of adipocytes with 100 nM isoproterenol, 30 ng/ml TNF alpha, and 100 nM insulin for 16 h significantly decreased ATGL mRNA to 74%, 17%, and 49% of control levels, respectively. GH did not influence ATGL synthesis. The effect of isoproterenol, TNFalpha, and insulin on ATGL expression was time- and dose-dependent. Similarly, HSL mRNA was downregulated by the three hormones. Furthermore, signaling studies suggested that activation of Gs-protein-coupled pathways by forskolin and cholera toxin is sufficient to significantly downregulate ATGL mRNA. Moreover, p44/42 mitogen-activated protein kinase appears to partly mediate the negative effect of insulin but not TNFalpha on ATGL. Taken together, downregulation of ATGL by isoproterenol, TNFalpha, and insulin might contribute to dysregulated expression and function of this lipase in obesity, hyperlipidemia, and insulin resistance.
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PMID:Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. 1600 85

Lipid droplets (LDs), also called adiposomes, are found in many eukaryotic cells, and are highly upregulated in lipid-storage cells, such as adipocytes. The mechanism by which adiposomes and their component neutral lipids are degraded is an important health issue with the rapidly spreading epidemic of obesity. Recently, a novel triglyceride lipase (adipose triglyceride lipase (ATGL)) that catalyses the initial step in triglyceride hydrolysis in adipocyte LDs was identified. Here, we show that ATGL also functions in non-adipocyte cells, and has an important role in LD degradation in these cells. Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. Depletion of ATGL by RNA interference leads to a significant increase in the size of LDs. These results show that ATGL has an important role in LD/adiposome turnover in mammalian cells.
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PMID:ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. 1623 26

The mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) and the recently characterized adipose triglyceride lipase (ATGL), yet their relative importance in lipolysis is unknown. We show that a novel potent inhibitor of HSL does not inhibit other lipases. The compound counteracted catecholamine-stimulated lipolysis in mouse adipocytes and had no effect on residual triglyceride hydrolysis and lipolysis in HSL-null mice. In human adipocytes, catecholamine- and natriuretic peptide-induced lipolysis were completely blunted by the HSL inhibitor. When fat cells were not stimulated, glycerol but not fatty acid release was inhibited. HSL and ATGL mRNA levels increased concomitantly during adipocyte differentiation. Abundance of the two transcripts in human adipose tissue was highly correlated in habitual dietary conditions and during a hypocaloric diet, suggesting common regulatory mechanisms for the two genes. Comparison of obese and nonobese subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes. In conclusion, HSL is the major lipase for catecholamine- and natriuretic peptide-stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression constitute a possibly primary defect in obesity.
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PMID:Adipocyte lipases and defect of lipolysis in human obesity. 1624 44

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

Catecholamines and natriuretic peptides stimulate human adipocyte lipolysis through an increase in cAMP and cGMP levels, resulting in phosphorylation and activation of hormone-sensitive lipase. A defect in hormone-sensitive lipase expression might contribute to the resistance to catecholamine-induced lipolysis observed in obesity. The respective roles and regulation of hormone-sensitive lipase and adipose triglyceride lipase in spontaneous and hormone-stimulated lipolysis remain to be determined. Tumor necrosis factor alpha stimulates triglyceride hydrolysis by multiple intracellular pathways acting on insulin signaling, G proteins and perilipins, and might contribute to enhanced plasma fatty acid levels in obesity. Characterization of the lipolytic pathways might provide novel strategies to decrease free fatty acid production and reverse insulin resistance and other obesity-related metabolic complications.
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PMID:Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. 1693 60

An excess of fat mass excess predisposes to multiple complications such as type 2 diabetes, cardiovascular diseases or cancer. A dysregulation of lipid metabolism contributes to the development of obesity and the metabolic syndrome. Recent data on lipid mobilization in adipose tissue have revealed a complex pathway involving a human specific hormonal control of lipolysis via the natriuretic peptides and a new triglyceride lipase, ATGL. Activation of fatty acid reesterification and oxidation can lead to an increase in fatty acid utilization. Targeting these key steps of lipid metabolism (adipose tissue lipolysis and fatty acid oxidation) constitutes a potential strategy for the treatment of obesity and associated metabolic disorders.
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PMID:[Fatty acid mobilization and their use in adipose tissue]. 1714 66

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.
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PMID:Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. 1727


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