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

Glucose, one of the most important nutrients for animals, acts as a regulatory signal that controls the secretion of hormones, such as insulin, by endocrine tissues. However, how organisms respond to extracellular glucose and how glucose controls nutrient homeostasis remain unknown. Here, we show that a putative Drosophila melanogaster G protein-coupled receptor, previously identified as Bride of sevenless (BOSS), responds to extracellular glucose and regulates sugar and lipid metabolism. We found that BOSS was expressed in the fat body, a nutrient-sensing tissue equivalent to mammalian liver and adipose tissues, and in photoreceptor cells. Boss null mutants had small bodies, exhibited abnormal sugar and lipid metabolism (elevated circulating sugar and lipid levels, impaired lipid mobilization to oenocytes), and were sensitive to nutrient deprivation stress. These phenotypes are reminiscent of flies defective in insulin signaling. Consistent with these findings are the observations that boss mutants had reduced PI3K activity and phospho-AKT levels, which indicates that BOSS is required for proper insulin signaling. Because human G protein-coupled receptor 5B and the seven-transmembrane domain of BOSS share the same sequence, our results also have important implications for glucose metabolism in humans. Thus, our study provides insight not only into the basic mechanisms of metabolic regulation but also into the pathobiological basis for diabetes and obesity.
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PMID:A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism. 1883 80

Reactive oxygen species (ROS) and insulin signaling in the adipose tissue are critical determinants of aging and age-associated diseases. It is not clear, however, if they represent independent factors or they are mechanistically linked. We investigated the effects of ROS on insulin signaling using as model system the p66(Shc)-null mice. p66(Shc) is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66(Shc) specifically in adipocytes and that p66(Shc)-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66(Shc) resulted in increased mitochondrial uncoupling and reduced triglyceride accumulation in adipocytes and in vivo increased metabolic rate and decreased fat mass and resistance to diet-induced obesity. In addition, p66(Shc-/-) mice showed impaired thermo-insulation. These findings demonstrate that p66(Shc)-generated ROS regulate the effect of insulin on the energetic metabolism in mice and suggest that intracellular oxidative stress might accelerate aging by favoring fat deposition and fat-related disorders.
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PMID:p66Shc-generated oxidative signal promotes fat accumulation. 1883 80

Recent investigations have demonstrated that activation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in liver and adipose tissue is closely related to the pathogenesis of obesity and diabetes. However, the relationship between alteration of 11beta-HSD1 and the pathogenesis of type 2 diabetes in skeletal muscle is still unclear. A rat model of Type 2 diabetes was developed by high fat diet feeding combined with multiple low dose streptozotocin injection (30 mg/kg, i.p. twice). Intraperitoneal glucose tolerance test, insulin tolerance test were performed. Fasting blood glucose, fasting insulin, total cholesterol, triglyceride were measured. The protein and mRNA level of 11beta-HSD1 and glucocorticoid receptor in gastrocnemius muscle were determined. The alteration of insulin signaling pathway related protein was investigated. We found that the protein levels of 11beta-HSD1 and glucocorticoid receptor were significantly increased (P < 0.05); the mRNA level of 11beta-HSD1 was also elevated (P < 0.05); the mRNA level of glucocorticoid receptor was decreased (P < 0.05). After insulin stimulation, diabetic rats had no significant changes in the level of the insulin receptor beta-subunit (IR-beta), AKT, as in phosphorylated AKT in the gastrocnemius muscle compared to its basal state. Similar results were observed in the protein expression level of glucose transporter 4 (GLUT4). Our data indicate that the alteration of 11beta-HSD1 at protein and mRNA level may be related to the abnormality of insulin signal pathway in skeletal muscle, this effect may be mediated by glucocorticoid receptor.
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PMID:Alteration of 11beta-hydroxysteroid dehydrogenase type 1 in skeletal muscle in a rat model of type 2 diabetes. 1911 9

Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin signaling transduction is important in endometrial cancer prevention and treatment. In this study, both isoforms of the leptin receptor (Ob-R), the long form (Ob-Rb) and short form (Ob-Ra), were detected as being expressed in six endometrial cancer cell lines with various differentiation status by western blotting, and Ob-Ra was found to be more abundant than Ob-Rb in these cells. Moreover, the expressions of both isoforms were inversely correlated with histoprognostic grading. We also showed that leptin stimulated cell proliferation and induced activations of signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK1/2), AKT, and cyclooxygenase (COX)-2 in endometrial cancer cells dose-dependently by [(3)H] thymidine incorporation assay and western blotting. Leptin-stimulation resulted in increased expression of COX-2 mRNA and prostaglandin E2 (PGE2) production of endometrial cancer cells by reverse transcription-polymerase chain reaction and enzyme immunoassay, respectively, which was effectively blocked by pharmacological inhibitors of Janus tyrosine kinase 2 (JAK2), AG490; of mitogen-activated protein kinase (MAPK) kinase, U0126; of phosphatidylinositol 3-kinase (PI3K), LY294002; and of COX-2, NS398. These results suggest that leptin promotes cell proliferation of endometrial cancer cells via the aforementioned multiple signal-transduction pathways. Leptin-induced functional activation of COX-2 is JAK2/STAT3-, MAPK/ERK-, and PI3K/AKT-dependent, indicating that COX-2 may be a critical factor of endometrial carcinogenesis in obesity.
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PMID:Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. 1915 13

Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean-CoPP, ZDF, and ZDF-CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF-CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.
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PMID:Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats. 1917 94

Infection with Trypanosoma cruzi, the etiologic agent of Chagas disease is accompanied by an intense inflammatory reaction. Our laboratory group has identified adipose tissue as one of the major sites of inflammation during disease progression. Because adipose tissue is composed of many cell types, we were interested in investigating whether the adipocyte per se was a source of inflammatory mediators in this infection. Cultured adipocytes were infected with the Tulahuen strain of T. cruzi for 48-96 h. Immunoblot and quantitative PCR (qPCR) analyses demonstrated an increase in the expression of proinflammatory cytokines and chemokines, including interleukin (IL)-1 beta, interferon-gamma, tumor necrosis factor-alpha, CCL2, CCL5, and CXCL10 as well as an increase in the expression of Toll-like receptors-2 and 9 and activation of the notch pathway. Interestingly, caveolin-1 expression was reduced while cyclin D1 and extracellular signal-regulated kinase (ERK) expression was increased. The expression of PI3kinase and the activation of AKT (phosphorylated AKT) were increased suggesting that infection may induce components of the insulin/IGF-1 receptor cascade. There was an infection-associated decrease in adiponectin and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These data provide a mechanism for the increase in the inflammatory phenotype that occurs in T. cruzi-infected adipocytes. Overall, these data implicate the adipocyte as an important target of T. cruzi, and one which contributes significantly to the inflammatory response observed in Chagas disease.
Obesity (Silver Spring) 2008 Sep
PMID:Trypanosoma cruzi infection of cultured adipocytes results in an inflammatory phenotype. 1918 25

Obesity is a risk factor for postmenopausal breast cancer (BC), but the specific mechanisms for this relationship are not well understood. Studies on adipocyte-derived adiponectin and leptin reveal opposing effects on BC cell proliferation in vitro, suggesting they may play a role in BC pathogenesis. In the current study we examined effects on proliferation of five BC cell lines treated with varying adiponectin:leptin (A/L) ratios. A decrease in proliferation was noted for MCF-7 and T47-D cells with increasing ratios (2-500), while an increase was seen in similarly treated MDA-MB-231 and MDA-MB-361 cells. For SK-BR-3 cells, an increase was seen at a ratio of 8. We identified differential effects on some pro-mitogenic, survival and apoptosis-related proteins in MCF-7 and T47-D cells treated at an A/L ratio of 100. Specifically, the AKT and MAPK pathways were not activated in MCF-7 cells, but AKT activation occured within 30 min and MAPK activation was sustained at 48 h in T47-D cells. p53 and Bax were elevated in MCF-7, but were below basal in T47-D cells at 30 min. While co-treatment enhanced apoptosis in MCF-7, similar treatment had the opposite effect in T47-D cells. There were no differences in cell cycle distribution between treated or untreated MCF-7 or T47-D, although T47-D cells had a slightly higher proportion in the G1/G0 phase after co-treatment. The effects of A/L ratio on mediating proliferation may have some specificity since the cell lines exhibited different responses. This may explain previous inconsistencies for the relationship of serum leptin with BC. More studies are needed to better understand the complex interactions that exist between these two adipokines.
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PMID:Effects of adiponectin and leptin co-treatment on human breast cancer cell growth. 1942 44

Energy balance and the AKT pathway are important in colorectal cancer development and regulate p27 (cyclin-dependent kinase inhibitor-1B/CDKN1B/KIP1), which plays a role in preventing cell cycle progression. However, little is known on the clinical outcome or prognostic significance of p27 alterations in relation to patient body mass index (BMI). Among 630 colon cancers (stage I-IV) in two prospective cohort studies, we detected p27 alterations (cytoplasmic p27 localization or p27 loss) in 500 tumors (79%) by immunohistochemistry. The remaining 130 (21%) tumors were "p27-nuclear+." Cox proportional hazard models computed hazard ratios (HR) of deaths, adjusted for patient and tumoral characteristics, including p53, p21, cyclin D1, KRAS, BRAF, PIK3CA, cyclooxygenase-2, fatty acid synthase (FASN), beta-catenin, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and long interspersed nucleotide element-1 (LINE-1) hypomethylation. Compared with p27-nuclear+ patients, p27-altered patients experienced low colon cancer-specific [adjusted HR, 0.63; 95% confidence interval (95% CI), 0.42-0.94] and overall mortality (adjusted HR, 0.70; 95% CI, 0.51-0.95), independent of FASN, MSI, CIMP, LINE-1 methylation, and other potential confounders. The effect of p27 alteration on overall mortality significantly differed by BMI (P(interaction) = 0.013); adjusted HR (p27-altered versus p27-nuclear+ tumors) was 0.28 (95% CI, 0.13-0.59) for BMI >or=30 kg/m(2), 0.67 (95% CI, 0.40-1.14) for BMI 25 to 29 kg/m(2), and 0.91 (95% CI, 0.57-1.46) for BMI <25 kg/m(2). Obesity was associated with inferior overall survival among p27-nuclear+ cases (adjusted HR, 3.07; 95% CI, 1.49-6.32; versus nonobese cases), but not among p27-altered cases (adjusted HR, 1.08). In conclusion, p27 alterations in colon cancer are associated with superior prognosis. Adverse prognostic effect of obesity seems limited to patients with nuclear p27 expression, suggesting a host-tumor interaction.
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PMID:A cohort study of p27 localization in colon cancer, body mass index, and patient survival. 1950 18

We investigated the role of leptin receptor (Ob-R) and its relationship with phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT-signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.
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PMID:Leptin receptor expression in Middle Eastern colorectal cancer and its potential clinical implication. 1952 Jul 93

Central leptin action requires PI3K activity to modulate glucose homeostasis and peripheral metabolism. However, the mechanism behind this phenomenon is not clearly understood. We hypothesize that hypothalamic PI3K activity is important for the modulation of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway, PGC1 alpha, and AKT in skeletal muscle (SM). To address this issue, we injected leptin into the lateral ventricle of rats. Hypothalamic JAK2 and AKT were activated by intracerebroventricular (ICV) injection of leptin in a time-dependent manner. Central leptin improved tolerance to glucose (GTT), increased PGC1 alpha expression, and AKT, AMPK, ACC and JAK2 phosphorylation in the soleus muscle. Previous ICV administration of either LY294002 or propranolol (IP) blocked these effects. We concluded that the activation of the hypothalamic PI3K pathway is important for leptin-induced AKT phosphorylation, as well as for active catabolic pathway through AMPK and PGC1 alpha in SM. Thus, a defective leptin signalling PI3K pathway in the hypothalamus may contribute to peripheral resistance to insulin associated to diet-induced obesity.
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PMID:Central leptin action improves skeletal muscle AKT, AMPK, and PGC1 alpha activation by hypothalamic PI3K-dependent mechanism. 1969 60


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