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)

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

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.
Obesity (Silver Spring) 2006 Aug
PMID:Adipose tissue as an endocrine organ. 1702 75

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

The objective of this work was to characterize the adaptation of cardiac metabolism to a lipid overload in a model of diet-induced obesity (DIO) in mice. After 8 wk dietary treatment, mice receiving a high-fat diet exhibited an increase in the amount of adipose tissue, accompanied by a surge in plasma leptin concentration (from 5.4-16.0 ng/ml). This was associated with: 1) an induction of uncoupling protein-2 (120%), 2) an increase in the phosphorylated form of AMP-activated protein kinase (120%), and 3) a reduction in lactate concentration and lactate dehydrogenase activity in myocardial tissue (40%). Because DIO induces leptin resistance, we analyzed leptin receptor functionality by measuring phospho-signal transducer and activator of transcription 3 in response to acute leptin (1 mg/kg). We observed that leptin receptor signaling remained unaltered within the heart but was fully impaired within the hypothalamus. Taken together, these data show that during DIO development, there is a metabolic shift in the heart aimed at increasing fatty acid oxidation to the detriment of carbohydrates. This effect seems to be leptin-dependent, suggesting that the increased adiposity observed during the onset of obesity might contribute to impairing ectopic lipidic deposition in the heart.
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PMID:Induction of cardiac uncoupling protein-2 expression and adenosine 5'-monophosphate-activated protein kinase phosphorylation during early states of diet-induced obesity in mice. 1730 71

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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PMID:Resveratrol improves health and survival of mice on a high-calorie diet. 1708 97

Compensatory beta cell growth occurs in accordance to overweight and increasing insulin demands. The proliferative actions of insulin and insulin-like growth factors are mediated via the IRS-2-PI(3)K-Akt pathway of pleiotropic insulin signaling. However, sustained activation leads to negative feedback via the mTOR-induced proteasomal degradation of IRS-2. The proliferative actions of incretins and adipokines are mediated via other pathways that ultimately converge with the IRS-2-PI(3)K-Akt axis. The incretins GIP and GLP-1 increase IRS-2 levels in beta cells by acting via the cAMP-PKA pathway, whereas leptin inhibits PTEN activity via CK2-dependent pathways. By increasing PIP(3) availability the adipokine amplifies the magnitude as well as duration of factors acting via the IRS-2-PI(3)K-Akt pathway. Considering that AMPK prevents mTOR-induced degradation of IRS-2, we propose that adiponectin and leptin cooperatively achieve compensatory beta cell growth in accordance to adiposity. In conditions of overt obesity, when adiponectin levels are too low to provide sufficient IRS-2 levels, loss of compensatory beta cell growth may occur.
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PMID:Leptin and adiponectin regulate compensatory beta cell growth in accordance to overweight. 1709 72

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

Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat.
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PMID:Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. 1712 73

Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.
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PMID:Brain adipocytokine action and metabolic regulation. 1713 Jun 38

Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined.
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PMID:Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. 1713 Jun 44


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