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)

Resistin has been proposed as a potential link between obesity and insulin resistance. It is also well established that altered metabolism of fatty acids by skeletal muscle can lead to insulin resistance and lipotoxicity. However, little is known about the effect of resistin on long chain fatty acid uptake and metabolism in skeletal muscle. Here we show that treating rat skeletal muscle cells with recombinant resistin (50 nM, 24 h) decreased uptake of palmitate. This correlated with reduced cell surface CD36 content and lower expression of FATP1, but no change in FATP4 or CD36 expression. We also found that resistin decreased fatty acid oxidation by measuring 14CO2 production from [1-14C] oleate and an increase in intracellular lipid accumulation was detected in response to resistin. Decreased AMPK and ACC phosphorylation were observed in response to resistin while expression of ACC and AMPK isoforms was unaltered. Resistin mediated these effects without altering cell viability. In summary, our results demonstrate that chronic incubation of skeletal muscle cells with resistin decreased fatty acid uptake and metabolism via a mechanism involving decreased cell surface CD36 content, FATP1 expression and a decrease in phosphorylation of AMPK and ACC.
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PMID:Regulation of fatty acid uptake and metabolism in L6 skeletal muscle cells by resistin. 1613 86

Chronic surplus of dietary consumption, typical to obesity, results in overflow of fat to non-adipose tissues. Intracellular accumulation of fat in non-adipose tissues is associated with cellular dysfunction and cell death and ultimately contributes to the pathogenesis of chronic diseases. The influence of fat overflow on the exocrine pancreas is not known. The purpose of this research was to study the lipotoxic and lipoapoptotic effect of prolonged (72 h) long chain saturated palmitic fatty acid (0.1 mM) on the survival of exocrine pancreas AR42J cells. We demonstrate that chronic exposure of AR42J cells to palmitic acid results in significant increase in triglycerides accumulation (up to 25% of cells area), compared to untreated cultures. Lipid accumulation prompted a typical apoptotic process, demonstrated by both DNA fragmentation and condensed chromatin appearance (DAPI staining). Quantitative real-time PCR studies demonstrated that prolonged palmitic acid supplementation induced down-regulation of the anti-apoptotic Bcl2 mRNA levels (22%) and up-regulation of the pro-apoptotic Bax mRNA levels (300%), leading to disruption of the pro/anti apoptotic balance (Bax/Bcl2=3). No major change was detected in iNOS mRNA expression. In conclusion, prolonged exposure to saturated palmitic acid induces lipoapoptosis in exocrine pancreatic AR42J cells, through disturbance of the Bax/Bcl-2 balance.
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PMID:Palmitate induced lipoapoptosis of exocrine pancreas AR42J cells. 1653 73

The genetic components of insulin-resistance, diabetes and obesity have been largely studied. These conditions are determined by multiple polygenic and environmental factors. Certain candidate genes, that have common functional variants in the general population, may be important determinants of inter-individual differences in the response to dietary changes. This review focuses in one of the major candidate genes, the gene encoding for the FABP2, an intracellular protein expressed only in the intestine, involved in the absorption and intracellular transport of dietary long chain fatty acids. Carriers of the Thr54 allele in FABP2 have a 2-fold greater affinity for long chain fatty acids than Ala54 carriers. The increased flux of dietary fatty acids (FA) into the circulation, among carriers of FABP2 Ala54Thr, supports a role of the polymorphism of this allele in the etiology of metabolic disorders. The frequencies of the polymorphism in different populations fluctuate between 18% and 40%. FABP2 Ala54Thr variant has been associated with an increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake. This evidence, although not conclusive, sustains an association between FABP-2 genotype and metabolic abnormalities.
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PMID:[Fatty acid binding protein 2 (FABP-2) polymorphism, obesity and insulin resistance]. 1667 13

In humans and animal models, increased intramuscular lipid (IML) stores have been implicated in insulin resistance. Malonyl-CoA plays a critical role in cellular lipid metabolism both by serving as a precursor in the synthesis of lipids and by inhibiting lipid oxidation. In muscle, Malonyl-CoA acts primarily as a negative allosteric regulator of carnitine palmitoyl transferase-1 (CPT1) activity, thereby blocking the transport of long chain fatty acyl CoAs into the mitochondria for oxidation. In muscle, increased malonyl-CoA, decreased muscle CPT1 activity, and increased IML have all been reported in obesity. In order to determine whether malonyl-CoA synthesis might be under transcriptional as well as biochemical regulation, we measured mRNA content of several key genes that contribute to the cellular metabolism of malonyl-CoA in muscle biopsies from lean to morbidly obese subjects. Employing quantitative real-time PCR, we determined that expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2) was increased by 50% with obesity (P < 0.05). In both lean and obese subjects, expression of mitochondrial ACC2 was 20-fold greater than that of cytoplasmic ACC1, consistent with their hypothesized roles in synthesizing malonyl-CoA from acetyl-CoA for CPT1 regulation and lipogenesis, respectively. In addition, in both lean and obese subjects, expression of malonyl-CoA decarboxylase was approximately 40-fold greater than fatty acid synthase, consistent with degradation, rather than lipogenesis, being the primary fate of malonyl-CoA in human muscle. No other genes showed signs of increased mRNA content with obesity, suggesting that there may be selective transcriptional regulation of malonyl-CoA metabolism in human obesity.
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PMID:Expression of genes regulating malonyl-CoA in human skeletal muscle. 1672 29

The objective of this study was to investigate the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)-induced AMP-activated protein kinase (AMPK) activation on basal and insulin-stimulated glucose and fatty acid metabolism in isolated rat adipocytes. AICAR-induced AMPK activation profoundly inhibited basal and insulin-stimulated glucose uptake, lipogenesis, glucose oxidation, and lactate production in fat cells. We also describe the novel findings that AICAR-induced AMPK phosphorylation significantly reduced palmitate (32%) and oleate uptake (41%), which was followed by a 50% reduction in palmitate oxidation despite a marked increase in AMPK and acetyl-CoA carboxylase phosphorylation. Compound C, a selective inhibitor of AMPK, not only completely prevented the inhibitory effect of AICAR on palmitate oxidation but actually caused a 2.2-fold increase in this variable. Compound C also significantly increased palmitate oxidation in the presence of inhibitory concentrations of malonyl-CoA and etomoxir indicating an increase in CPT1 activity. In contrast to skeletal muscle in which AMPK stimulates fatty acid oxidation to provide ATP as a fuel, we propose that AMPK activation inhibits lipogenesis and fatty acid oxidation in adipocytes. Inhibition of lipogenesis would conserve ATP under conditions of cellular stress, although suppression of intra-adipocyte oxidation would spare fatty acids for exportation to other tissues where their utilization is crucial for energy production. Additionally, the stimulatory effect of compound C on long chain fatty acid oxidation provides a novel pharmacological approach to promote energy dissipation in adipocytes, which may be of therapeutic importance for obesity and type II diabetes.
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PMID:5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes. 1681 4

Topiramate (TPM) is a novel neurotherapeutic agent approved for the treatment of epilepsy and for migraine prophylaxis. It has been observed that in obese-associated, type 2 diabetic rodent models, TPM treatment reduced the body weight gain, improved insulin sensitivity, and enhanced glucose-regulated insulin release. A long-term treatment with TPM thus ameliorated obesity and diabetic syndromes in female Zucker diabetic fatty rats and db/db mice. The molecular mechanisms of TPM antiobesity and antidiabetic effects remain unknown. We have applied DNA microarray technology to explore genes that might be involved in the mechanisms by which TPM improves insulin sensitivity and blood glucose handling, as well as body weight control. In female Zucker diabetic fatty rats, 7-day TPM treatment significantly reduced the plasma levels of glucose and triglyceride in a dose-dependent manner. The DNA microarray data revealed that TPM treatment altered messenger RNA profiles in liver, hypothalamus, white adipose tissue, and skeletal muscle. The most marked effect of TPM on gene expression occurred in liver with those genes related with metabolic enzymes and signaling regulatory proteins involved in energy metabolism. TPM treatment decreased messenger RNA amounts for sterol regulatory element binding protein-1c, stearoyl-coenzyme A (CoA) desaturase-1, choline kinase, and fatty acid CoA ligase, long chain 4. TPM also up-regulated 3 cholesterol synthesis genes. In addition, the short-term effect of TPM on gene expression was examined at 16 hours after a single administration. TPM markedly reduced hepatic expression of genes related with fatty acid synthesis, eg, stearoyl-CoA desaturase and acetyl-CoA carboxylase. TPM also changed genes related with fatty acid beta-oxidation, increased 3-2-trans-enoyl-CoA isomerase and mitochondrial acyl-CoA thioesterase, and decreased fatty acid CoA ligase (long chain 2 and long chain 5). These gene expression changes were independent of food intake as shown by pair feeding. Our results suggest that TPM regulates hepatic expression of genes involved in lipid metabolism, which could be part of the mechanisms by which TPM reduces plasma triglyceride levels in obese diabetic rodents.
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PMID:The messenger RNA profiles in liver, hypothalamus, white adipose tissue, and skeletal muscle of female Zucker diabetic fatty rats after topiramate treatment. 1697 14

Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to levels witnessed in lean controls. Previous reports have suggested that obesity-related insulin resistance stems from lipid oversupply and tissue accumulation of toxic lipid intermediates that impair insulin signaling. We reasoned that contraction might activate hydrolysis and oxidation of intramuscular lipids, thus alleviating "lipotoxicity" and priming the muscle for enhanced insulin action. Indeed, analysis of mitochondrial-derived acyl-carnitine esters suggested that contraction caused robust increases in beta-oxidative flux and mitochondrial oxidation. As predicted, contraction decreased intramuscular triacylglycerol content; however, diacylglycerol and long chain acyl-CoAs, lipid intermediates presumed to trigger insulin resistance, were either unchanged or increased. In muscles from obese animals, insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 remained impaired after contraction, whereas phosphorylation of the downstream signaling protein, AS160, was partially restored. These results suggest that acute exercise enables diabetic muscle to circumvent upstream defects in insulin signal transduction via mechanisms that are more tightly coupled to increased mitochondrial energy metabolism than the lowering of diacylglycerol and long chain acyl-CoA.
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PMID:Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism. 1705 Jun 16

Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
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PMID:Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. 1712 22

We proposed that inhibition of mitochondrial adenine nucleotide translocator (ANT) by long chain acyl-CoA (LCAC) underlies the mechanism associating obesity and type 2 diabetes. Here we test that after long-term exposure to a high-fat diet (HFD): (i) there is no adaptation of the mitochondrial compartment that would hinder such ANT inhibition, and (ii) ANT has significant control of the relevant aspects of oxidative phosphorylation. After 7 weeks, HFD induced a 24+/-6% increase in hepatic LCAC concentration and accumulation of the oxidative stress marker N(epsilon)-(carboxymethyl)lysine. HFD did not significantly affect mitochondrial copy number, oxygen uptake, membrane potential (Deltapsi), ADP/O ratio, and the content of coenzyme Q(9), cytochromes b and a+a(3). Modular kinetic analysis showed that the kinetics of substrate oxidation, phosphorylation, proton leak, ATP-production and ATP-consumption were not influenced significantly. After HFD-feeding ANT exerted considerable control over oxygen uptake (control coefficient C=0.14) and phosphorylation fluxes (C=0.15), extra- (C=0.23) and intramitochondrial (C=-0.56) ATP/ADP ratios, and Deltapsi (C=-0.11). We conclude that although HFD induces accumulation of LCAC and N(epsilon)-(carboxymethyl)lysine, oxidative phosphorylation does not adapt to these metabolic challenges. Furthermore, ANT retains control of fluxes and intermediates, making inhibition of this enzyme a more probable link between obesity and type 2 diabetes.
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PMID:Functioning of oxidative phosphorylation in liver mitochondria of high-fat diet fed rats. 1718 76

The development of hypothalamic leptin resistance plays a role in the development of obesity, yet whether peripheral leptin resistance occurs in obesity and diabetes is controversial. Here we investigate whether hyperinsulinemia, as observed during the development of Type 2 diabetes, modifies the effects of leptin on long chain fatty acid metabolism in skeletal muscle cells. We used boron dipyrromethene difluoride (BODIPY)-labeled palmitate to show that leptin (60 nM) caused a time-dependent (0-60 min) increase in fatty acid uptake in L6 myoblasts. Quantitative analysis using 3H-palmitate showed that pre-incubation with insulin (100 nM, 24 h) prevented stimulation of fatty acid uptake by leptin. Insulin pre-treatment also attenuated the ability of leptin to phosphorylate acetyl Co-A carboxylase and increase palmitate oxidation. Suppressor of cytokine-3 (SOCS-3) has been proposed as a possible mediator of insulin-induced leptin resistance. Here we show that treatment of L6 cells with insulin elicited a time-dependent increase in both SOCS-3 mRNA and protein content. In summary, hyperinsulinemia can induce leptin resistance in L6 myoblasts and this may be mediated via a SOCS-3-dependent mechanism.
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PMID:Control of fatty acid metabolism by leptin in L6 rat myoblasts is regulated by hyperinsulinemia. 1750 51


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