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Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice.

ABSTRACT: OBJECTIVE: Recent genome-wide association studies have identified a strong association between obesity and common variants in the fat mass and obesity associated (FTO) gene. FTO has been detected in the hypothalamus, but little is known about its regulation in that particular brain structure. The present study addressed the hypothesis that hypothalamic FTO expression is regulated by nutrients, specifically by glucose, and that its regulation by nutrients is impaired in obesity. RESEARCH DESIGN AND METHODS: The effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of glucose on hypothalamic Fto mRNA levels was examined in fasted mice. Additionally, the effect of glucose on Fto mRNA levels was also investigated ex vivo using mouse hypothalamic explants. Lastly, the effect of i.p. glucose injection on hypothalamic Fto immunoreactivity and food intake was compared between lean wild-type and obese ob/ob mice. RESULTS: In wild-type mice, fasting reduced both Fto mRNA levels and the number of Fto-immunoreactive cells in the hypothalamus, whereas i.p. glucose treatment reversed this effect of fasting. Furthermore, i.c.v. glucose treatment also increased hypothalamic Fto mRNA levels in fasted mice. Incubation of hypothalamic explants at high glucose concentration increased Fto mRNA levels. In ob/ob mice, both fasting and i.p. glucose treatment failed to alter the number of Fto-immunoreactive cells in the hypothalamus. Glucose-induced feeding suppression was abolished in ob/ob mice. CONCLUSION: Reduction in hypothalamic Fto expression after fasting likely arises at least partly from reduced circulating glucose levels and/or reduced central action of glucose. Obesity is associated with impairments in glucose-mediated regulation of hypothalamic Fto expression and anorexia. Hypothalamic Fto-expressing neurons may have a role in the regulation of metabolism by monitoring metabolic states of the body.

SUBMITTER: Poritsanos NJ

PROVIDER: S-EPMC3302139 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice.

Poritsanos N J NJ Lew P S PS Fischer J J Mobbs C V CV Nagy J I JI Wong D D Rüther U U Mizuno T M TM

Nutrition & diabetes 20111031

<h4>Objective</h4>Recent genome-wide association studies have identified a strong association between obesity and common variants in the fat mass and obesity associated (FTO) gene. FTO has been detected in the hypothalamus, but little is known about its regulation in that particular brain structure. The present study addressed the hypothesis that hypothalamic FTO expression is regulated by nutrients, specifically by glucose, and that its regulation by nutrients is impaired in obesity.<h4>Researc ...[more]

PMID: 23154321

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Project description:BACKGROUND:Around 308 million people worldwide are estimated to have impaired glucose tolerance (IGT); 25% to 75% of these will develop diabetes within a decade of initial diagnosis. At diagnosis, half will have tissue-related damage and all have an increased risk for coronary heart disease. OBJECTIVES:The objective of this review was to assess the effects and safety of Chinese herbal medicines for the treatment of people with impaired glucose tolerance or impaired fasting glucose (IFG). SEARCH STRATEGY:We searched the following databases: The Cochrane Library, PubMed, EMBASE, AMED, a range of Chinese language databases, SIGLE and databases of ongoing trials. SELECTION CRITERIA:Randomised clinical trials comparing Chinese herbal medicines with placebo, no treatment, pharmacological or non-pharmacological interventions in people with IGT or IFG were considered. DATA COLLECTION AND ANALYSIS:Two authors independently extracted data. Trials were assessed for risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, outcome assessors and intervention providers, incomplete outcome data, selective outcome reporting and other sources of bias. MAIN RESULTS:This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial (RR 0.33; 95% CI 0.19 to 0.58). However, all trials had a considerable risk of bias and none of the specific herbal medicines comparison data was available from more than one study. Moreover, results could have been confounded by rates of natural reversion to normal glucose levels. AUTHORS' CONCLUSIONS:The positive evidence in favour of Chinese herbal medicines for the treatment of IGT or IFG is constrained by the following factors: lack of trials that tested the same herbal medicine, lack of details on co-interventions, unclear methods of randomisation, poor reporting and other risks of bias.

Project description:To determine insulin resistance and response in patients with polycystic ovary syndrome (PCOS) and normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance (CGI).In this cross-sectional study, 143 patients with PCOS (diagnosed on the basis of National Institutes of Health criteria) underwent oral glucose tolerance testing (OGTT), and 68 patients also had frequently sampled intravenous glucose tolerance tests. Changes in plasma glucose, insulin, cardiovascular risk factors, and androgens were measured.Compared with patients with NGT, those with both IFG and CGI were significantly insulin resistant (homeostasis model assessment 3.3 +/- 0.2 vs. 6.1 +/- 0.9 and 6.4 +/- 0.5, P < 0.0001) and hyperinsulinemic (insulin area under the curve for 120 min 973 +/- 69 vs. 1,470 +/- 197 and 1,461 +/- 172 pmol/l, P < 0.0001). Insulin response was delayed in patients with CGI but not in those with IFG (2-h OGTT, insulin 1,001 +/- 40 vs. 583 +/- 45 pmol/l, P < 0.0001). Compared with the NGT group, the CGI group had a lower disposition index (1,615 +/- 236 vs. 987 +/- 296, P < 0.0234) and adiponectin level (11.1 +/- 1.1 vs. 6.2 +/- 0.8 ng/ml, P < 0.0096). Compared with the insulin-resistant tertile of the NGT group, those with IFG had a reduced insulinogenic index (421 +/- 130 vs. 268 +/- 68, P < 0.05). Compared with the insulin-sensitive tertile of the NGT group, the resistant tertile had higher triglyceride and high-sensitivity C-reactive protein (hs-CRP) and lower HDL cholesterol and sex hormone-binding globulin (SHBG). In the entire population, insulin resistance correlated directly with triglyceride, hs-CRP, and the free androgen index and inversely with SHBG.Patients with PCOS develop IFG and CGI despite having significant hyperinsulinemia. Patients with IFG and CGI exhibit similar insulin resistance but very different insulin response patterns. Increases in cardiac risk factors and free androgen level precede overt glucose intolerance.

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Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice.

Publications

Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice.

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