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)

Licorice flavonoid oil (LFO), which contains hydrophobic flavonoids from Glycyrrhiza glabra LINNE, is a new ingredient for functional foods. In this study, we investigated the anti-obesity action of LFO in diet-induced obese rats. The addition of 2% LFO in a high-fat diet significantly decreased the weight of abdominal adipose tissue and the levels of hepatic and plasma triglycerides. We found that the enzymatic activities of acetyl-CoA carboxylase and fatty acid synthase, the rate-limiting enzymes in the fatty acid synthetic pathway, were significantly decreased by LFO, whereas the enzymatic activity of acyl-CoA dehydrogenase, the rate-limiting enzyme in the fatty acid oxidative pathway, was significantly increased. All our findings suggest that the anti-obesity action of LFO is controlled by regulation of the rate-limiting enzymes in the fatty acid synthetic and oxidative pathways in the liver.
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PMID:Investigation of the anti-obesity action of licorice flavonoid oil in diet-induced obese rats. 1906 Apr 15

High-fat (HF) diets can induce insulin resistance (IR) by altering skeletal muscle lipid metabolism. An imbalance between fatty acid (FA) uptake and oxidation results in intramuscular lipid accumulation, which can impair the insulin-signaling cascade. Adiponectin (Ad) is an insulin-sensitizing adipokine known to stimulate skeletal muscle FA oxidation and reduce lipid accumulation. Evidence of Ad resistance has been shown in obesity and following chronic HF feeding and may contribute to lipid accumulation observed in these conditions. Whether Ad resistance precedes and is associated with the development of IR is unknown. We conducted a time course HF feeding trial for 3 days, 2 wk, or 4 wk to determine the onset of Ad resistance and identify the ensuing changes in lipid metabolism and insulin signaling leading to IR in skeletal muscle. Ad stimulated FA oxidation (+28%, P < or = 0.05) and acetyl-CoA carboxylase phosphorylation (+34%, P < or = 0.05) in control animals but failed to do so in any HF-fed group (i.e., as early as 3 days). By 2 wk, plasma membrane FA transporters and intramuscular diacylglycerol (DAG) and ceramide were increased, and insulin-stimulated phosphorylation of both protein kinase B and protein kinase B substrate 160 was blunted compared with control animals. After 4 wk of HF feeding, maximal insulin-stimulated glucose transport was impaired compared with control. Taken together, our results demonstrate that an early loss of Ad's stimulatory effect on FA oxidation precedes an increase in plasmalemmal FA transporters and the accumulation of intramuscular DAG and ceramide, blunted insulin signaling, and ultimately impaired maximal insulin-stimulated glucose transport in skeletal muscle induced by HF diets.
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PMID:Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats. 1907

Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP(-/-)) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP(-/-) mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP(-/-) mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP(-/-) mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP(-/-) mice, which could in part account for the metabolic phenotype in KRAP(-/-) mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.
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PMID:Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice. 1915 25

Beta-Aminoisobutyric acid (BAIBA), a thymine catabolite, increases fatty acid oxidation (FAO) in liver and reduces the gain of body fat mass in Swiss (lean) mice fed a standard chow. We determined whether BAIBA could prevent obesity and related metabolic disorders in different murine models. To this end, BAIBA (100 or 500 mg/kg/day) was administered for 4 months in mice totally deficient in leptin (ob/ob). BAIBA (100 mg/kg/day) was also given for 4 months in wild-type (+/+) mice and mice partially deficient in leptin (ob/+) fed a high-calorie (HC) diet. BAIBA did not limit obesity and hepatic steatosis in ob/ob mice, but reduced liver cytolysis and inflammation. In ob/+ mice fed the HC diet, BAIBA fully prevented, or limited, the gain of body fat, steatosis and necroinflammation, glucose intolerance, and hypertriglyceridemia. Plasma beta-hydroxybutyrate was increased, whereas expression of carnitine palmitoyltransferase-1 was augmented in liver and white adipose tissue. Acetyl-CoA carboxylase was more phosphorylated, and de novo lipogenesis was less induced in liver. These favorable effects of BAIBA in ob/+ mice were associated with a restoration of plasma leptin levels. The reduction of body adiposity afforded by BAIBA was less marked in +/+ mice. Finally, BAIBA significantly stimulated the secretion of leptin in isolated ob/+ adipose cells, but not in +/+ cells. Thus, BAIBA could limit triglyceride accretion in tissues through a leptin-dependent stimulation of FAO. As partial leptin deficiency is not uncommon in the general population, supplementation with BAIBA may help to prevent diet-induced obesity and related metabolic disorders in low leptin secretors.
Obesity (Silver Spring) 2008 Sep
PMID:Beta-aminoisobutyric acid prevents diet-induced obesity in mice with partial leptin deficiency. 1918 30

This study investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in the regulation of lipolysis in visceral (VC) and subcutaneous (SC) rat adipocytes and the molecular mechanisms involved in this process. VC (epididymal and retroperitoneal) and SC (inguinal) adipocytes were isolated from male Wistar rats (160-180 g). Adipocytes were incubated either in the absence or in the presence of the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR, 0-500 micromol/l). AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, basal and epinephrine-stimulated (100 nmol/l) glycerol release, and hormone-sensitive lipase (HSL) phosphorylation and activity were determined. AICAR-induced (500 micromol/l) AMPK activation inhibited basal glycerol release by approximately 42, 41, and 44% in epididymal, retroperitoneal, and inguinal adipocytes, respectively. Epinephrine-stimulated glycerol release was almost completely prevented by AICAR treatment in adipocytes from all fat depots. The AMPK inhibitor compound C (20 micromol/l) prevented AICAR-induced phosphorylation of AMPK and significantly increased basal (approximately 1.3-, 1.4-, and 1.7-fold) and epinephrine-stimulated (approximately 1.3-, 1.2-, 1.4-fold) glycerol release in epididymal, retroperitoneal, and inguinal adipocytes, respectively. AICAR increased phosphorylation of HSL(Ser565) and inhibited epinephrine-induced phosphorylation of HSL(Ser563) and HSL(Ser660). This was also accompanied by a 73% reduction in epinephrine-stimulated HSL activity. Compound C prevented the phosphorylation of HSL(Ser565) induced by AICAR and partially prevented the inhibitory effect of this drug on basal and epinephrine-stimulated lipolysis in adipocytes in VC and SC fat depots. In summary, despite different fat depots eliciting distinct rates of lipolysis, acute AICAR-induced AMPK activation suppressed HSL phosphorylation/activation and exerted similar antilipolytic effects on both VC and SC adipocytes.
Obesity (Silver Spring) 2009 Jul
PMID:Regulation of visceral and subcutaneous adipocyte lipolysis by acute AICAR-induced AMPK activation. 1921 74

Maternal nutrient restriction (NR) from early to midgestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may reset the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the obese adult offspring. NR offspring were exposed to an "obesogenic" environment, and their cardiac function and molecular indexes of myocardial energy metabolism were assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed 100% (control) or 50% (NR) energy requirement from days 30 to 80 of gestation and 100% energy requirement thereafter. At weaning, offspring were exposed to an obesogenic environment or remained lean. At approximately 1 yr of age, the hemodynamic response of these offspring to hypotension, together with left ventricular expression profiles of fatty acid-binding protein 3 (FABP3), peroxisome proliferator-activated receptor-gamma (PPARgamma) and its coactivator (PGC)-1alpha, acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)-alpha(2), and voltage-dependent anion channel 1 (VDAC1), was determined. Obesity produced left ventricular hypertrophy in all animals, with increased ectopic (myocardial) lipid in NR offspring. Obesity per se significantly reduced myocardial transcript expression of PGC-1alpha, AMPKalpha(2), VDAC1, and ACC and increased expression of PPARgamma and FABP3. However, although NR animals were similarly obese, their transcript expression of ACC, PPARgamma, and FABP3 was similar to that of lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotropic response to hypotension characterized cardiac function in obese NR offspring. The results suggest that maternal NR during early organogenesis can precipitate an altered myocardial response to hypotension and increased myocardial lipid deposition in the adult offspring after adolescent-onset obesity, potentially rendering these individuals more at risk of early heart failure as they age.
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PMID:Effect of maternal nutrient restriction from early to midgestation on cardiac function and metabolism after adolescent-onset obesity. 1924 82

In the brain malonyl-CoA serves the important function of monitoring and modulating energy balance. Because of its central role in the metabolism of higher animals, glucose acts as the principal indicator of global energy status. Specialized neuronal nuclei within the hypothalamus sense blood glucose and signal higher brain centers to adjust feeding behavior and energy expenditure accordingly. As the level of glucose entering the brain rises, food intake is suppressed. Energy status information triggered by glucose is transmitted via hypothalamic signaling intermediaries, i.e. AMPK and malonyl-CoA, to the orexigenic/anorexigenic neuropeptide system that determines hunger and energy expenditure. The central metabolism of glucose by the glycolytic pathway generates ATP which produces a compensatory decrease in AMP level and AMPK activity. Since acetyl-CoA carboxylase (ACC) is a substrate of AMPK, lowering AMP increases the catalytic activity of ACC and thereby, the level of its reaction product, malonyl-CoA. Malonyl-CoA signals the anorexigenic-orexigenic neuropeptide system to suppress food intake. Unlike glucose, however, centrally metabolized fructose increases food intake. This paradox results because fructose bypasses the rate-limiting step of glycolysis and uses a rapid ATP-requiring reaction that abruptly depletes ATP and provokes a compensatory rise in AMP. Thus, fructose has the opposite effect of glucose on the AMPK/malonyl-CoA signaling system and thereby, feeding behavior. The fact that fructose metabolism by the brain increases food intake and obesity risk raises health concerns in view of the large and increasing per capita consumption of high fructose sweeteners, especially by youth.
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PMID:Effect of glucose and fructose on food intake via malonyl-CoA signaling in the brain. 1978 93

Layer and broiler chickens demonstrate striking differences in body weight and body composition. However, the mechanism underlying such difference is elusive. Hypothalamus-pituitary-adrenal (HPA) axis regulates energy homeostasis and body size in mammals, but information in birds is scarce. Here we test the hypothesis that such breed difference is more associated with hypothalamic expression of genes related to HPA axis, rather than orexigenic neuropeptides. Broiler chicks exhibit significantly higher body weight and food intake at day (D) 7 posthatching, but the food intake relative to body weight gain was actually lower. No breed differences were observed for hypothalamic expression of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), orexin (ORX), leptin receptor (LEPR), acetyl-CoA carboxylase (ACC) or fatty acid synthase (FAS). However, broiler chicks expressed significantly higher glucocorticoid receptor (GR) mRNA (P<0.05) and protein (P<0.01) in hypothalamus compared to layer chicks, which is associated with lower corticotropin-releasing hormone (CRH) mRNA (P<0.05) yet higher accumulation of CRH peptide in hypothalamus, suggesting an augmented GR-mediated negative feedback regulation of CRH transcription and release in broiler chicks. Furthermore, fat mass and obesity associated (FTO) gene was also more highly expressed in hypothalamus of broiler chicks (P<0.05). These results suggest that the genes related to energy homeostasis and obesity, such as GR, CRH and FTO, rather than orexigenic neuropeptides, are impacted by the genetic selection practices and play a role in breed-specific body weight setpoint regulation in the chicken.
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PMID:Layer and broiler chicks exhibit similar hypothalamic expression of orexigenic neuropeptides but distinct expression of genes related to energy homeostasis and obesity. 1934 99

We established a new animal model called SPORTS (Spontaneously-Running Tokushima-Shikoku) rats, which show high-epinephrine (Epi) levels. Recent reports show that Epi activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) in adipocytes. Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis, and the enzymatic activity is suppressed when its Ser-79 is phosphorylated by AMPK. The aim of this study was to investigate the in vivo effect of Epi on ACC and abdominal visceral fat accumulation. We divided both 6-week male control and SPORTS rats into two groups, which were fed either normal diet or high fat and sucrose (HFS) diet for 16 weeks. At the end of diet treatment, retroperitoneal fat was collected for western blotting and histological analysis. Food intake was not different among the groups, but SPORTS rats showed significantly lower weight gain than control rats in both diet groups. After 10 weeks of diet treatment, glucose tolerance tests (GTTs) revealed that SPORTS rats had increased insulin sensitivity. Furthermore, SPORTS rats had lower quantities of both abdominal fat and plasma triglyceride (TG). In abdominal fat, elevated ACC Ser-79 phosphorylation was observed in SPORTS rats and suppressed by an antagonist of beta-adrenergic receptor (AR), propranolol, or an inhibitor of AMPK, Compound C. From these results, high level of Epi induced ACC phosphorylation mediated through beta-AR and AMPK signaling pathways in abdominal visceral fat of SPORTS rats, which may contribute to reduce abdominal visceral fat accumulation and increase insulin sensitivity. Our results suggest that beta-AR-regulated ACC activity would be a target for treating lifestyle-related diseases, such as obesity.
Obesity (Silver Spring) 2010 Jan
PMID:Beta-adrenergic-AMPK pathway phosphorylates acetyl-CoA carboxylase in a high-epinephrine rat model, SPORTS. 1944 33

Catechins are abundant in green tea and induce a variety of biologic actions, including anti-cancer, anti-obesity, and anti-diabetes effects, and their clinical application has been widely investigated. To clarify the underlying molecular mechanisms of these actions, we examined the effect of catechins on AMP-activated protein kinase (AMPK) in cultured cells and in mice. In Hepa 1-6, L6, and 3T3-L1 cells, epigallocatechin gallate (EGCG) induced increases in AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC) phosphorylation, and AMPKalpha activity. Analysis of the molecular specificity of eight naturally occurring catechins revealed that catechins with a gallocatechin moiety or a galloyl residue act as AMPK activators. In addition, phosphorylation of LKB1, which is a tumor-suppressor protein and a major AMPK-kinase, was increased by catechin treatment. EGCG-induced phosphorylation of LKB1 and AMPKalpha was suppressed by treatment with catalase, suggesting that reactive oxygen species are involved in EGCG-induced activation of the LKB1/AMPK pathway. Oral administration of EGCG (200mg/kg body weight) to BALB/c mice induced an increase in AMPKalpha activity in the liver concomitant with a significant increase in AMPKalpha and ACC phosphorylation. EGCG administration also increased oxygen consumption and fat oxidation, as determined by indirect calorimetry. These findings suggest that multiple effects of catechins, including anti-obesity and anti-cancer effects, are mediated, at least in part, by the activation of LKB1/AMPK in various tissues, and that these effects vary according to the catechin structure.
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PMID:Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway. 1944 26


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