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

N J Poritsanos,T M Mizuno,C V Mobbs,U Rüther,D Wong,J I Nagy,P S Lew,J Fischer

doi:10.1038/nutd.2011.15

N J Poritsanos, T M Mizuno + Show 6 more

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https://doi.org/10.1038/nutd.2011.15

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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.

Highlights

Recent genome-wide association studies have identified a strong association between obesity and common variants in the fat mass and obesity-associated (FTO) gene.[1]
Consistent with reports describing widespread Fto mRNA expression in the central nervous system, Fto-immunoreactive Nutrition and Diabetes cells were found in many areas of the mouse brain, including various areas in the hypothalamus that are involved in the regulation of energy balance.[6,7,8,9]
The association between FTO variants and obesity raises the possibility that Fto has a role in the regulation of metabolism and that expression of hypothalamic Fto may be regulated by nutritional signals

Summary

Introduction

Recent genome-wide association studies have identified a strong association between obesity and common variants in the fat mass and obesity-associated (FTO) gene.[1]. FTO is expressed in various tissues, including the hypothalamus where its levels are especially high.[1,6,7,8] Hypothalamic Fto mRNA levels are altered by fasting, and hypothalamic Fto-expressing cells are activated by feeding.[6,7,8,9,10] Of particular interest, contrary to the metabolic phenotypes of Fto-deficient mice and Fto-overexpressing mice, targeted reduction of Fto expression in the hypothalamic arcuate

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Conclusion