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

Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.
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PMID:[The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism]. 1450 Nov 64

Hyperphagia was achieved by continuous intracerebroventricular infusion of a melanocortin receptor antagonist (HS024; Neosystem, Strasbourg, France) in rats. The effects of hyperphagia on FA composition and concentration of plasma phospholipids (PL), plasma FFA, and adipose tissue TAG were studied in rats for 8 d [short-term hyperphagia (STH); n = 8], or 28 d [long-term hyperphagia (LTH); n = 9]. The control rats were treated with artificial cerebrospinal fluid for 8 d (n = 8) or 28 d (n = 10). The rats were fed the same regular diet. In STH rats the plasma PL and fasting plasma FFA contained higher concentrations of saturated FA (SFA) and monounsaturated FA (MUFA), and plasma FFA contained lower n-6 PUFA than in the control rats. In LTH rats the plasma PL contained higher concentrations of SFA, MUFA, and n-3 PUFA and higher proportions of 16:1n-7 and 18:1n-9 at the expense of 18:2n-6 than in the control rats. In LTH rats the abundant dietary intake of 18:2n-6 did not enrich 18:2n-6 of the plasma PL or adipose tissue TAG. In LTH rats the fasting plasma FFA contained more than twofold higher concentrations of SFA and MUFA, and higher proportions of 16:1n-7 and 18:1n-9 at the expense of 18:2n-6 than in the control rats. This animal obesity model shows that LTH affects the FA composition and concentration of plasma PL, plasma FFA, and adipose tissue TAG, a result consistent with changes associated with increased risk of various diseases in humans. These results also demonstrate that LTH alters the FA composition of plasma PL and adipose tissue TAG in a way that does not reflect the FA composition of dietary fat.
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PMID:Hyperphagia modifies FA profiles of plasma phospholipids, plasma FFA, and adipose tissue TAG. 1473 57

Elevated FFA concentrations have been shown to reproduce some of the metabolic abnormalities of obesity. It has been hypothesized that visceral adipose tissue lipolysis releases excess FFAs into the portal vein, exposing the liver to higher FFA concentrations. We used isotope dilution/hepatic vein catheterization techniques to examine whether intra-abdominal fat contributes a greater portion of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n = 20) with a range of obesity phenotypes, taken together with healthy, lean women (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA kinetics were measured. The results showed that plasma FFA concentrations were approximately 20% greater in obese men and obese women. The contribution of splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost 50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002) and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater portion of systemic FFA release in obese men and women than in lean men and women. We conclude that the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery increases with increasing visceral fat in humans and that this effect is greater in women than in men.
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PMID:Splanchnic lipolysis in human obesity. 1517 78

The resistin gene is expressed in adipocytes and encodes a protein proposed to link obesity and type 2 diabetes. Increased plasma FFA is associated with insulin resistance. We examined the effect of separate FFAs on the expression of resistin mRNA in cultured murine 3T3-L1 adipocytes. The FFAs tested did not increase resistin expression, whereas both arachidonic acid (AA) and eicosapentaenoic acid (EPA) reduced resistin mRNA levels. AA was by far the most potent FFA, reducing resistin mRNA levels to approximately 20% of control at 60-250 muM concentration. Selective inhibitors of cyclooxygenase-1 and of mitogen-activated protein kinase kinase counteracted AA-induced reduction in resistin mRNA levels. Transient overexpression of sterol-regulatory element binding protein-1a (SREBP-1a) activated the resistin promoter, but there was no reduction in the abundance of approximately 65 kDa mature SREBP-1 after AA exposure. Actinomycin D as well as cycloheximide abolished the AA-induced reduction of resistin mRNA levels, indicating dependence on de novo transcription and translation. Our data suggest that reductions in resistin mRNA levels involve a destabilization of the resistin mRNA molecule. An inhibitory effect of AA and EPA on resistin expression may explain the beneficial effect of ingesting PUFAs on insulin sensitivity.
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PMID:Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid. 1548 40

Glucose-6-phosphate dehydrogenase (G6PD) produces cellular NADPH, which is required for the biosynthesis of fatty acids and cholesterol. Although G6PD is required for lipogenesis, it is poorly understood whether G6PD in adipocytes is involved in energy homeostasis, such as lipid and glucose metabolism. We report here that G6PD plays a role in adipogenesis and that its increase is tightly associated with the dysregulation of lipid metabolism and insulin resistance in obesity. We observed that the enzymatic activity and expression levels of G6PD were significantly elevated in white adipose tissues of obese models, including db/db, ob/ob, and diet-induced obesity mice. In 3T3-L1 cells, G6PD overexpression stimulated the expression of most adipocyte marker genes and elevated the levels of cellular free fatty acids, triglyceride, and FFA release. Consistently, G6PD knockdown via small interfering RNA attenuated adipocyte differentiation with less lipid droplet accumulation. Surprisingly, the expression of certain adipocytokines such as tumor necrosis factor alpha and resistin was increased, whereas that of adiponectin was decreased in G6PD overexpressed adipocytes. In accordance with these results, overexpression of G6PD impaired insulin signaling and suppressed insulin-dependent glucose uptake in adipocytes. Taken together, these data strongly suggest that aberrant increase of G6PD in obese and/or diabetic subjects would alter lipid metabolism and adipocytokine expression, thereby resulting in failure of lipid homeostasis and insulin resistance in adipocytes.
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PMID:Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. 1592 30

Resistin has been postulated to play a role in obesity-related insulin resistance. To explore this possibility, we have investigated effects of acute euglycemic (5.2+/-0.1 mmol/L) hyperinsulinemia (96+/-8 microU/mL) with and without concurrent infusion of lipid plus heparin (to raise or lower plasma free fatty acid [FFA] levels) on glucose turnover and plasma resistin levels in alert rats. Plasma FFA concentrations increased during lipid/heparin (L/H) infusion (from 0.82 to 2.86 mmol/L, P<.001) and decreased (from 0.83 to 0.21 mmol/L, P<.001) in controls who were infused with insulin but not with L/H. L/H infusion reduced insulin suppression of endogenous glucose production by approximately 90% (from 28.9 to 3.1 mg. kg-1 . min-1, P<.001) and insulin-stimulated glucose uptake (glucose rate of disappearance) by 78% (from 30.8% to 6.9%, P<.001). Plasma resistin levels increased by 46% (from 39.9 to 58.4 microg/L, P<.05) during L/H infusion and did not change in controls (39.7 vs 39.3 microg/L). Plasma ghrelin levels decreased by 41% (from 892 to 584 ng/L, P<.05) in response to hyperinsulinemia, whereas concurrent L/H infusion had no additional effect on ghrelin levels (584+/-67 vs 548+/-82 ng/L). In summary, we found that FFA induced hepatic insulin resistance, and to a lesser extent, peripheral insulin resistance was associated with elevated plasma resistin levels. We conclude that FFA-induced release of resistin may contribute to the development of FFA-induced insulin resistance in rats.
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PMID:Effects of free fatty acids on plasma resistin and insulin resistance in awake rats. 1612 24

The aim of the present study was to analyze whether consumption of a fiber-supplemented diet containing 3.5% Plantago ovata husks prevented many of the abnormalities clustered in the metabolic syndrome, including obesity, dyslipidemia, hypertension and endothelial dysfunction. For this purpose, obese Zucker rats, a model of type 2 diabetes, and their lean littermates were studied. Rats consumed a standard control diet or that diet supplemented with 3.5% P. ovata husks for 25 wk. Body weights were measured weekly. Systolic blood pressure (SBP) was measured monthly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, FFAs, glucose, insulin, adiponectin, and tumor necrosis factor alpha (TNF-alpha) were determined, and studies on vascular function were performed using aortic rings. Rats fed the P. ovata husk-supplemented diet had a significantly reduced body weight gain compared with those fed the standard diet. Decreased endothelium-dependent relaxation in response to acetylcholine (ACh) by aortic rings from obese Zucker rats was improved in those fed the fiber-supplemented diet. The greater SBP, higher plasma concentrations of triglycerides, total cholesterol, FFA, glucose, insulin, and TNF-alpha, and the hypoadinectinemia that occurred in obese Zucker rats that consumed the control diet were significantly improved in those fed the fiber-supplemented diet. We conclude that intake of a P. ovata husk-supplemented diet prevents endothelial dysfunction, hypertension, and obesity development, and ameliorates dyslipidemia and abnormal plasma concentrations of adiponectin and TNF-alpha in obese Zucker rats.
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PMID:A diet supplemented with husks of Plantago ovata reduces the development of endothelial dysfunction, hypertension, and obesity by affecting adiponectin and TNF-alpha in obese Zucker rats. 1617 3

The G protein G(s)alpha is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G(s)-signaling pathways by developing mice with liver-specific G(s)alpha deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARgamma coactivator-1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide-1 levels and pancreatic alpha cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic G(s)-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.
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PMID:Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency. 1623 68

All treatments for obesity, including dietary restriction of carbohydrates, have a goal of reducing the storage of fat in adipocytes. The chief enzyme responsible for the mobilization of FFA from adipose tissue, i.e., lipolysis, is thought to be hormone-sensitive lipase (HSL). Studies of HSL knockouts have provided important insights into the functional significance of HSL and into adipose metabolism in general. Studies have provided evidence that HSL, though possessing triacylglycerol lipase activity, appears to be the rate-limiting enzyme for cholesteryl ester and diacylglycerol hydrolysis in adipose tissue and is essential for complete hormone stimulated lipolysis, but other triacylglycerol lipases are important in mediating triacylglycerol hydrolysis in lipolysis. HSL knockouts are resistant to both high fat diet-induced and genetic obesity, displaying reduced quantities of white with increased amounts of brown adipose tissue, increased numbers of adipose macrophages, and have multiple alterations in the expression of genes involved in adipose differentiation, including transcription factors, markers of adipocyte differentiation, and enzymes of fatty acid and triglyceride synthesis. With disruption of lipolysis by removal of HSL, there is a drastic reduction in lipogenesis and alteration in adipose metabolism.
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PMID:Hormone-sensitive lipase knockouts. 1647 89

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels (P < 0.001) with hepatic venous resistin being higher than arterial levels (P < 0.001). Circulating resistin was significantly correlated with plasma TNF-alpha levels (r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production (r = -0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies (r = 0.48, P < 0.001) as well as hepatic ketone body production (r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved (P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis.
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PMID:Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance. 1647 79


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