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

Adiponectin is thought to play a decisive role in the relationships among obesity, insulin resistance and cardiovascular risk. This study investigated whether cardiomyocytes synthesize and secrete adiponectin, and the effects of this hormone on cardiac cells. RT-PCR showed that mouse, rat and human cardiomyocytes produced mRNA for adiponectin and adiponectin receptors 1 and 2. Immunohistochemistry confirmed the presence of adiponectin in the cytoplasm of cultured cardiomyocytes, and radioimmunoassay showed that these cells secreted adiponectin into the culture medium. Exogenous adiponectin enhanced glucose and fatty acid uptake and induced AMPK phosphorylation in cultured cardiomyocytes. Our results demonstrate that adiponectin is synthesized and secreted by isolated murine and human cardiomyocytes, and suggest that the local production of this hormone by cardiomyocytes could be involved in the regulation of cardiac metabolism and function.
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PMID:Adiponectin is synthesized and secreted by human and murine cardiomyocytes. 1614 Feb 97

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
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PMID:Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. 1635 80

Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease.
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PMID:miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. 1645 10

Adipose tissue is an active endocrine organ producing a variety of cytokines and chemokines, which may be involved in the deregulation of glucose and lipid homeostasis as well as in the inflammatory state observed in obesity. We have shown previously that differentiated human adipocytes secrete a variety of cytokines which are able to induce skeletal muscle insulin resistance. However, the regulation of these factors by anti-diabetic drugs has remained mainly undefined. Secretion of IL-6, IL-8, MIP-1alpha/beta, and MCP-1 by adipocytes was found to be downregulated by adiponectin. In parallel to adiponectin, the AMPK activator AICAR also decreased the secretion of most of the measured cytokines including IL-6 and MIP-1alpha/beta but not IL-8. In contrast, the thiazolidinedione troglitazone only slightly reduced cytokine secretion despite increasing the phosphorylation of AMPK. In conclusion, we show that adipocyte secretion is strongly inhibited by the anti-diabetic adipocyte hormone adiponectin, an effect that can also be mimicked by the AMPK activator AICAR. However, the PPARgamma agonist troglitazone is much less effective in reducing cytokine secretion.
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PMID:Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. 1656 50

Increased de novo lipogenesis and reduced fatty acid oxidation are probable contributors to adipose accretion in obesity. Moreover, these perturbations have a role in leading to non-alcoholic steatohepatitis, dyslipidemia, and insulin resistance--via "lipotoxicity"-related mechanisms. Research in this area has prompted an effort to evaluate several discrete enzymes in these pathways as targets for future therapeutic intervention. Acetyl-CoA carboxylase 1 (ACC1) and ACC2 regulate fatty acid synthesis and indirectly control fatty acid oxidation via a key product, malonyl CoA. Based on mouse genetic and preclinical pharmacologic evidence, inhibition of ACC1 and/or ACC2 may be a useful approach to treat obesity and metabolic syndrome. Similarly, available data suggest that inhibition of other enzymes in this pathway, including fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol acytransferase 1, will have beneficial effects. AMP-activated protein kinase is a master regulator of nutrient metabolism, which controls several aspects of lipid metabolism. Activation of AMPK in selected tissues is also a potential therapeutic approach. Inhibition of hormone-sensitive lipase is another possible approach. The rationale for modulating the activity of these enzymes and their relative merits (and downsides) as possible therapeutic targets are further discussed.
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PMID:Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. 1662 96

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory gamma subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.
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PMID:AMP-activated protein kinase--development of the energy sensor concept. 1664

Plant flavonoids are widely distributed polyphenolic compounds of the human diet. They consist of six major classes based on specific structural differences: flavonols, flavones, flavanones, catechins, anthocyanidins, and isoflavones. All of the major classes of flavonoids are comprised of three six-membered rings: an aromatic A-ring fused to a heterocyclic C-ring that is attached through a single carbon-carbon bond to an aromatic Bring. Population studies have shown that flavonoid intake is inversely correlated with mortality from cardiovascular disease, and numerous flavonoids of dietary significance have been shown to beneficially impact parameters associated with atherosclerosis, including lipoprotein oxidation, blood platelet aggregation, and vascular reactivity. Therapeutic effects of flavonoids on platelet aggregability and blood pressure have been attributed to competitive inhibition of cyclic nucleotide phosphodiesterase (PDE), an elevation in cAMP level, and subsequent activation of protein kinase A (cAMP-dependent protein kinase). In addition, flavonoids may induce neutral lipid hydrolysis from lipid stores through PDE inhibition in adipose tissue and liver. Indeed, the three-dimensional structure of many flavonoids is sterically and electrostatically compatible with the catalytic site of cAMP PDE3 and PDE4. Flavonoids have also been reported to suppress pathways of lipid biosynthesis and of very low-density lipoprotein production in cultured hepatocytes. Continued studies of the biochemical mechanisms underlying the biological effects of plant flavonoids may uncover new strategies for the treatment of cardiovascular disease, as well as associated conditions such as obesity, hepatic steatosis, and Type 2 diabetes.
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PMID:Flavonoids attenuate cardiovascular disease, inhibit phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. 1694 97

AMP-activated protein kinase plays an important role in the regulation of lipid metabolism in response to metabolic stress and energy demand. It is also under endocrine control. AMPK acts at multiple steps and has a central role controlling fatty acid, triglyceride, and cholesterol synthesis, as well as the oxidation of fatty acids through direct phosphorylation effects and the control of gene transcription. As such, it can be considered to be the fat controller of the energy railroad. It is thought that AMPK may be a major mediator of the health benefits of exercise in mitigating the development of obesity and age-onset diseases.
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PMID:AMP-activated protein kinase--the fat controller of the energy railroad. 1699 29

The target of rapamycin (TOR) pathway regulates ribosome biogenesis, protein synthesis, nutrient import, autophagy and cell cycle progression. After 30 years of concentrated attention, how TOR controls these processes is only now beginning to be understood. Recent advances have identified a wide array of TOR inputs, including amino acids, oxygen, ATP and growth factors, as well the regulatory proteins that facilitate their effects on TOR. Such proteins include AMPK, Rheb and the tumor suppressors LKB1, p53, and Tsc1/2. It has only recently been appreciated that TOR resides in two distinct signaling complexes with differing regulatory roles, only one of which is rapamycin-sensitive, thus opening a new avenue of inquiry into TOR function. Finally, TOR appears to regulate feeding behavior by facilitating communication between organ systems, and is thus implicated in the regulation of glucose and fat homeostasis, and possibly diabetes and obesity. TOR thus functions to coordinate growth-permitting inputs with growth-promoting outputs on both a cellular and an organismal level.
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PMID:Thinking globally and acting locally with TOR. 1704 29


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