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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic beta cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARalpha signaling. Administration of a PPARalpha agonist into the hypothalamus increased PPARalpha target genes and normalized food intake. Inactivation of beta cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARalpha. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARalpha (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance.
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PMID:Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. 1769 78

Leptin-deficient ob/ob mice are a murine model for obesity, insulin resistance, and diabetes. Here we report that non-lethal abdominal irradiation (a single fraction of 850 cGy) to ob/ob mice retarded rapid gain of body weight, leading to amelioration of obesity without marked changes in food intake. This effect was observed only in ob/ob mice and not in lean controls. Reduction of body weight was accompanied by decreased adipose tissue weight without any marked change in the size of adipocytes, indicating prevention of hyperplasia rather than hypertrophy. Gene expression of the radiation-inducible cdk-inhibitor, p21, and the adipocytokines, tumor necrosis factor alpha and interleukin-1beta, were induced as expected; but genes involved in adipogenesis such as peroxisome proliferator-activated receptor gamma and adipsin were not affected in the irradiated adipose tissue. Inversely, hepatic lipid content was elevated with concomitant increases in the expression of lipogenic enzymes such as fatty acid synthase (FAS), and sterol regulatory element-binding protein 1c. Despite the decreased adiposity, there was no improvement in hyperglycemia and hyperinsulinemia after the irradiation. In conclusion, abdominal irradiation to ob/ob mice affected the progression of obesity and altered the energy metabolism between organs through a novel mechanism, implicating a new approach or factor for understanding and treatment of obesity.
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PMID:Abdominal Irradiation Ameliorates Obesity in ob/ob Mice. 1818 14

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser(428), and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKbeta, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.
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PMID:SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. 1848 75

Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia), a peroxisome proliferator activated receptor (gamma-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kg x bw) for 12 weeks (n = 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P < 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the beta-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase (SCD1). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-gamma and tumor necrosis factor alpha (TNF-alpha).
Exp Clin Endocrinol Diabetes 2008 Jun
PMID:Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis. 1870 Feb 76

Diabetes mellitus (DM) is a common endocrine disease in cats and dogs with increasing prevalence. Type 1 DM appears to be the most common form of diabetes in dogs whereas Type 2 DM prevails for cats. Since insulin resistance is more frequently encountered in cats than dogs, our laboratory was interested in determining whether differences at the insulin signaling pathway level and differences in glucose and lipid metabolism could be observed between cats and dogs. Insulin resistance has been positively correlated to insulin signaling pathway abnormalities. As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85alpha mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. Different tissues were sampled because it is currently unknown where insulin-resistance arises from. In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. No distinct expression pattern emerged; however, differences were noted between canines and felines. In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85alpha mRNA expression levels which would predispose cats to develop insulin resistance. Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. Therefore, a combination of genetic and environmental factors appears to make felines more prone to suffer from insulin resistance and type 2 DM than canines.
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PMID:Comparison of insulin signaling gene expression in insulin sensitive tissues between cats and dogs. 1904 94

Risk of developing obesity and diabetes may be influenced by the nutritional environment early in life. We examined the effects of high fibre or protein diets on satiety hormones and genes involved in glucose and lipid metabolism during postnatal development and on adult fat mass. At 21 days of age, Wistar rat pups were weaned onto control (C), high fibre (HF) or high protein (HP) diet. Tissue and blood were collected at 7, 14, 21, 28 and 35 days after birth. A second group of rats consumed the weaning diets until 4 months when they were switched to a high fat-high sugar diet for 6 weeks, after which body and fat mass and plasma glucose were determined. In young rats, HF diet increased plasma glucagon-like peptide (GLP-1) compared to C and HP and decreased leptin compared to C at postnatal days 28 and 35. Hepatic fatty acid synthase mRNA was down-regulated by HF and HP compared to C at days 28 and 35. In brown adipose tissue, HF increased uncoupling protein-3 mRNA whereas HP increased mRNA of the inflammatory cytokine interleukin-6. Body weight, fat mass and glycaemia in adult males and fat mass in females were greater after the high fat challenge in rats that consumed the HP diet from weaning. Increasing fibre or protein in postnatal diets causes rapid change in satiety hormone secretion and genes involved in glucose and lipid metabolism which appear to influence fat mass and glycaemia in adulthood, high protein being associated with increased susceptibility to obesity.
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PMID:Changes in satiety hormones and expression of genes involved in glucose and lipid metabolism in rats weaned onto diets high in fibre or protein reflect susceptibility to increased fat mass in adulthood. 1906 20

Genistein, an isoflavone, was shown to have therapeutic effects for obesity, diabetes and cardiovascular diseases. This study investigated the effect and underlying mechanism of genistein on adipogenesis in 3T3-L1 preadipocytes. Genistein inhibited lipid accumulation and decreased the nonesterified fatty acid (NEFA) content of 3T3-L1 on day 6 after the induction of differentiation with methylisobutylxanthine, dexamethasone and insulin (MDI). Genistein recovered nitric oxide (NO) release suppressed by MDI and the results were consistent with the expression of endothelial NO synthase (eNOS) assayed by western blotting. Pretreatment with genistein inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) stimulated with 10 microg/mL of insulin. Furthermore, genistein inhibited the expression of fatty acid synthase (FAS) from 178% of the MDI group to 74%. SB203580, a p38 inhibitor, mimicked the FAS inhibition effect of genistein, suggesting that the inhibitory effect of genistein on FAS was partially via the p38 pathway. On the other hand, genistein abolished the phosphorylation of janus-activated kinase 2 (JAK2) in response to MDI. AG490, a JAK2 inhibitor, suppressed the expression of CCAAT/enhancer binding protein alpha (C/EBPalpha), a marker of adipocyte differentiation. The findings suggest that genistein attenuates the differentiation of 3T3-L1 involving multiple signal pathways.
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PMID:Genistein suppresses adipogenesis of 3T3-L1 cells via multiple signal pathways. 1910 52

Accumulation of lipids in the heart may cause cardiac dysfunction in various disorders, such as obesity and diabetes. In the current study, we have investigated whether administration of angiotensin II or norepinephrine induces accumulation of lipids and/or changes in the expression of genes related to lipid metabolism in the rat heart. Lipid deposition was found in myocardial, vascular wall, and perivascular cells of the angiotensin II-infused rat heart, and superoxide generation was increased in these lipid-positive cells. By contrast, intracardiac lipid deposition was not found in the heart of norepinephrine-induced hypertensive rats. Triglyceride content in the heart tissue of angiotensin II-infused rats increased more than 3-fold as compared with untreated controls. Losartan completely, but hydralazine only partially, suppressed the angiotensin II-induced intracardiac lipid deposition and increase in tissue triglyceride content. Administration of angiotensin II upregulated the mRNA expression of sterol regulatory element-binding protein-1c and fatty acid synthase, but downregulated that of uncoupling protein 2 and 3, in a manner dependent on the angiotensin AT(1) receptor. Collectively, these results suggest that angiotensin II may be involved in modulating both intracardiac lipid content and lipid metabolism-related gene expression, in part via an angiotensin AT(1) receptor-dependent and pressor-independent mechanism.
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PMID:Administration of angiotensin II, but not catecholamines, induces accumulation of lipids in the rat heart. 1910 42

The effects of a pumpkin paste concentrate and its components on oral glucose tolerance and serum lipid levels were determined in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. In the oral glucose tolerance test, the pumpkin paste concentrate-fed group maintained a lower glucose level than the control group between 15 and 60 min. The compounds considered to be effective in improving glucose tolerance and contained in the methanol extract of the pumpkin in relatively abundant amounts were isolated and identified as trigonelline (TRG) and nicotinic acid (NA).Feeding a diet containing TRG and NA respectively improved and tended to improve glucose tolerance. The insulin level increased after 15 min in the TRG-fed GK rats and then gradually decreased over the next 120 min. In contrast, a gradual increase was seen in the insulin level over 120 min in the control GK rats not fed with TRG, suggesting that TRG could improve the insulin resistance. The serum and liver triglyceride (TG) levels in the TRG- and NA-fed GK rats were lower than those in the control GK rats. Lower activity of liver fatty acid synthase (FAS), and higher activity of liver carnitine palmitoyl transferase (CPT) and glucokinase (GLK) in the TRG- and NA-fed GK rats than in the control GK rats were observed. This suggests that the regulation of these enzyme activities by TRG and NA was closely related to the suppression of both TG accumulation and the progression of diabetes.
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PMID:Anti-diabetic effects of pumpkin and its components, trigonelline and nicotinic acid, on Goto-Kakizaki rats. 1942 Jul 12

Contradictory findings regarding the gene expression of the main lipogenic enzymes in human adipose tissue depots have been reported. In this cross-sectional study, we aimed to evaluate the mRNA expression of fatty acid synthase (FAS) and acetyl-CoA carboxilase (ACC) in omental and subcutaneous (SC) fat depots from subjects who varied widely in terms of body fat mass. FAS and ACC gene expression were evaluated by real time-PCR in 188 samples of visceral adipose tissue which were obtained during elective surgical procedures in 119 women and 69 men. Decreased sex-adjusted FAS (-59%) and ACC (-49%) mRNA were found in visceral adipose tissue from obese subjects, with and without diabetes mellitus type 2 (DM-2), compared with lean subjects (both P < 0.0001). FAS mRNA was also decreased (-40%) in fat depots from overweight subjects (P < 0.05). Indeed, FAS mRNA was significantly and positively associated with ACC gene expression (r = 0.316, P < 0.0001) and negatively with BMI (r = -0.274), waist circumference (r = -0.437), systolic blood pressure (r = -0.310), serum glucose (r = -0.277), and fasting triglycerides (r = -0.226), among others (all P < 0.0001). Similar associations were observed for ACC gene expression levels. In a representative subgroup of nonobese (n = 4) and obese women (n = 6), relative FAS gene expression levels significantly correlated (r = 0.657, P = 0.034; n = 10) with FAS protein values. FAS protein levels were also inversely correlated with blood glucose (r = -0.640, P = 0.046) and fasting triglycerides (r = -0.832, P = 0.010). In conclusion, the gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue from obese subjects.
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PMID:The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. 1954 3


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