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

Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic triglyceride stores in non-adipose tissues such as muscles, liver and pancreatic beta-cells. A high cytosolic triglyceride content is accompanied by elevated concentrations of cytosolic long-chain acyl-CoA esters, the metabolically active form of fatty acids. These esters inhibit mitochondrial adenine nucleotide translocators, resulting in an intramitochondrial ADP deficiency. In vitro, such ADP deficiency is a potent stimulator of mitochondrial oxygen free radical production, and we assume that this mechanism is also active in vivo. The decline of organ function with normal ageing is thought to be due, at least partly, to a continuous low-grade mitochondrial oxygen free radical production. In tissues containing increased cytosolic triglyceride stores this process will be accelerated. Tissues with a high-energy demand or poor free radical scavenging capacity, such as pancreatic beta-cells, are likely to be more susceptible to this process. This is how we explain their gradual dysfunctioning in central obesity. Likewise we propose that the enhanced production of oxygen free radicals in endothelial cells, or vascular smooth muscle cells, leads to the increased subendothelial oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction and microalbuminuria.
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PMID:Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure? 1058 Jan 66

The peroxisomal 3-oxoacyl-CoA thiolase (thiolase) is the last enzyme involved in the beta-oxidation of fatty acids. The enzyme cleaves long chain fatty acyl-CoA to generate acetyl-CoA and shortened acyl-CoA. The enzyme is nuclear encoded, synthesized in the cytoplasm and transported into peroxisomes. The thiolase B gene is inducible by the peroxisome proliferator compounds, like other genes involved in beta-oxidation of fatty acids in peroxisomes. The importance of studying thiolase is that it generates acetyl-CoA which is the precursor for the synthesis of molecules like cholesterol and fatty acids. The structural and functional analysis of thiolase at molecular level may add to the knowledge of fatty acid metabolism and further the obesity phenomenon. It is known that several genes mediate lipid homeostasis in target organs like liver, adipose tissue and are regulated by peroxisome proliferator activated receptors (PPAR alpha and PPAR gamma). To elucidate the mechanism of induction of rat liver thiolase B gene, an upstream 2.8 kb fragment containing promoter element has been subcloned and partially sequenced. The sequence analysis revealed a putative PPRE (Peroxisome Proliferator Response Element) of AGACCT T TGAACC sequence at -681 to -668 [Kliever et al. (1992) Nature 358:771-774]. By transient expression of a luciferase reporter gene in HeLa cells, we conclude that the identified PPRE could be functional in induction of thiolase B gene, but other sequences of genes might be involved.
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PMID:Studies on regulation of the peroxisomal beta-oxidation at the 3-ketothiolase step. Dissection of the rat liver thiolase B gene promoter. 1070 52

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.
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PMID:Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. 1080 41

A lipolytic domain (AOD9401) of human growth hormone (hGH) which resides in the carboxyl terminus of the molecule and contains the amino acid residues 177-191, has been synthesized using solid-phase peptide synthesis techniques. AOD9401 stimulated hormone-sensitive lipase and inhibited acetyl coenzyme A carboxylase (acetyl CoA carboxylase) in isolated rat adipose tissues, in a similar manner to the actions of the intact hGH molecule. The synthetic lipolytic domain mimicked the effect of the intact growth hormone on diacylglycerol release in adipocytes. Chronic treatment of obese Zucker rats with AOD9401 for 20 days reduced the body weight gain of the animals, and the average cell size of the adipocytes of the treated animals decreased from 110 to 80 microm in diameter. Unlike hGH, synthetic AOD9401 did not induce insulin resistance or glucose intolerance in the laboratory animals after chronic treatment. The results suggest that AOD9401 has the potential to be developed into a therapeutic agent for the control of obesity.
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PMID:Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. 1111 8

Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. The decline in food intake, body weight, and body fat in old rats was only 25%, 50%, and 16%, respectively, of the young rats. Whereas in young rats plasma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadipocyte factor 1 increased dramatically and leptin mRNA virtually disappeared; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activated receptor alpha, accounting for the reduction in body fat. These hyperleptinemia-induced changes were profoundly reduced in the old rats. On a high-fat diet, old rats consumed 28% more calories than the young and gained 1.5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (SOCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was approximately 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly.
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PMID:The role of leptin resistance in the lipid abnormalities of aging. 1114 98

Because triglycerides are considered essential for survival and their synthesis has been thought to occur through a single mechanism, inhibiting triglyceride synthesis has been largely unexplored as a possible target for obesity treatment. However, recent studies indicate that mice lacking acyl CoA:diacylglycerol acyltransferase (DGAT), a key enzyme in triglyceride synthesis, are viable and resistant to diet-induced obesity. Unexpectedly, this resistance is caused by a mechanism involving increased energy expenditure. These findings suggest that inhibiting specific components of triglyceride synthesis, such as DGAT, is feasible and may represent a novel approach to treating obesity.
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PMID:DGAT and triglyceride synthesis: a new target for obesity treatment? 1128 93

Endogenous lipid stores are thought to be involved in the mechanism whereby the beta-cell adapts its secretory capacity in obesity and diabetes. In addition, hormone-sensitive lipase (HSL) is expressed in beta-cells and may provide fatty acids necessary for the generation of coupling factors linking glucose metabolism to insulin release. We have recently created HSL-deficient mice that were used to directly assess the role of HSL in insulin secretion and action. HSL(-/-) mice were normoglycemic and normoinsulinemic under basal conditions, but showed an approximately 30% reduction of circulating free fatty acids (FFAs) with respect to control and heterozygous animals after an overnight fast. An intraperitoneal glucose tolerance test revealed that HSL-null mice were glucose-intolerant and displayed a lack of a rise in plasma insulin after a glucose challenge. Examination of plasma glucose during an insulin tolerance test suggested that HSL-null mice were insulin-resistant, because plasma glucose was barely lowered after the injection of insulin. Freshly isolated islets from HSL-deficient mice displayed elevated secretion at low (3 mmol/l) glucose, failed to release insulin in response to high (20 mmol/l) glucose, but had a normal secretion when challenged with elevated KCl. The phenotype of heterozygous mice with respect to the measured parameters in vitro was similar to that of wild type. Finally, the islet triglyceride content of HSL(-/-) mice was 2-2.5 fold that in HSL(-/+) and HSL(+/+) animals. The results demonstrate an important role of HSL and endogenous beta-cell lipolysis in the coupling mechanism of glucose-stimulated insulin secretion. The data also provide direct support for the concept that some lipid molecule(s), such as FFAs, fatty acyl-CoA or their derivatives, are implicated in beta-cell glucose signaling.
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PMID:A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. 1152 61

We hypothesized that certain proteins encoded by temperature-responsive genes in brown adipose tissue (BAT) contribute to the remarkable metabolic shifts observed in this tissue, thus prompting a differential mRNA expression analysis to identify candidates involved in this process in mouse BAT. An mRNA species corresponding to a novel partial-length gene was found to be induced 2-3-fold above the control following cold exposure (4 degrees C), and repressed approximately 70% by warm acclimation (33 degrees C, 3 weeks) compared with controls (22 degrees C). The gene displayed robust BAT expression (i.e. approximately 7-100-fold higher than other tissues in controls). The full-length murine gene encodes a 594 amino acid ( approximately 67 kDa) open reading frame with significant homology to the human hypothetical acyl-CoA thioesterase KIAA0707. Based on cold-inducibility of the gene and the presence of two acyl-CoA thioesterase domains, we termed the protein brown-fat-inducible thioesterase (BFIT). Subsequent analyses and cloning efforts revealed the presence of a novel splice variant in humans (termed hBFIT2), encoding the orthologue to the murine BAT gene. BFIT was mapped to syntenic regions of chromosomes 1 (human) and 4 (mouse) associated with body fatness and diet-induced obesity, potentially linking a deficit of BFIT activity with exacerbation of these traits. Consistent with this notion, BFIT mRNA was significantly higher ( approximately 1.6-2-fold) in the BAT of obesity-resistant compared with obesity-prone mice fed a high-fat diet, and was 2.5-fold higher in controls compared with ob/ob mice. Its strong, cold-inducible BAT expression in mice suggests that BFIT supports the transition of this tissue towards increased metabolic activity, probably through alteration of intracellular fatty acyl-CoA concentration.
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PMID:BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity. 1169

ATP sensitive potassium (K(ATP)) channels reside in the plasma membrane of many excitable cells such as pancreatic beta-cells, heart, skeletal muscle and brain, where they link cellular metabolic energy to membrane electrical activity. They are composed of two subunits, K+ ion selective pore (Kir) and sulfonylurea receptor (SUR). In addition to the central role of pancreatic beta-cell K(ATP) channels in glucose-mediated insulin secretion, several lines of evidence support the hypothesis that K(ATP) channels modulate glucose transport in the insulin target tissues. Inhibition of K(ATP) channels by glibenclamide or gliclazide or an increase in intracellular ATP during hyperglycemia (glucose effect) or exercise facilitates glucose utilization, while activation of the channels by potassium channel openers, hypothermia (cardiac surgery), or ischemic damage (myocardial and brain infarction) reduces glucose uptake induced by insulin or hyperglycemia. Because insulin action has been known to depend on the energy level of the target cells, K(ATP) channel may function as an effector in this respect. It is now evident that long chain acyl-CoA esters, metabolically active forms of fatty acids, are the most potent and physiologically important activator of K(ATP) channels. Thus, I suppose that the sustained activation of K(ATP) channels by long chain fatty acyl-CoA seems to be a missing link between lipotoxicity and insulin resistance in obesity and type 2 diabetes mellitus.
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PMID:Adenosine triphosphate-sensitive potassium (K(ATP)) channel activity is coupled with insulin resistance in obesity and type 2 diabetes mellitus. 1186 13

beta(3)-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. beta(3)-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, beta(3)-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify beta(3)-adrenoceptor agonist drugs because the pharmacology of both beta(3)- and beta(1)-adrenoceptors can vary; near absolute selectivity is needed to avoid beta(1/2)-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. beta(3)-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling.
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PMID:beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. 1200 28


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