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Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis


BACKGROUND/OBJECTIVES: Glucose from the diet may signal metabolic status to hypothalamic sites controlling energy homeostasis.Disruption of this mechanism may contribute to obesity but its relevance has not been established. The present experiments aimed atevaluating whether obesity induced by chronic high-fat intake affects the ability of hypothalamic glucose to control feeding. Wehypothesized that glucose transport to the hypothalamus as well as glucose sensing and signaling could be impaired by high-fat feeding.SUBJECTS/METHODS: Female Wistar rats were studied after 8 weeks on either control or high-lard diet. Daily food intake wasmeasured after intracerebroventricular (i.c.v.) glucose. Glycemia and glucose content of medial hypothalamus microdialysates weremeasured in response to interperitoneal (i.p.) glucose or meal intake after an overnight fast. The effect of refeeding on wholehypothalamus levels of glucose transporter proteins (GLUT) 1, 2 and 4, AMPK and phosphorylated AMPK levels was determined byimmunoblotting.RESULTS: High-fat rats had higher body weight and fat content and serum leptin than control rats, but normal insulin levels andglucose tolerance. I.c.v. glucose inhibited food intake in control but failed to do so in high-fat rats. Either i.p. glucose or refeedingsignicantly increased glucose hypothalamic microdialysate levels in the control rats. These levels showed exacerbated increases inthe high-fat rats. GLUT1 and 4 levels were not affected by refeeding. GLUT2 levels decreased and phosphor-AMPK levels increasedin the high-fat rats but not in the controls.CONCLUSIONS: The ndings suggest that, in the high-fat rats, a defective glucose sensing by decreased GLUT2 levels contributedto an inappropriate activation of AMPK after refeeding, despite increased extracellular glucose levels. These derangements wereprobably involved in the abolition of hypophagia in response to i.c.v. glucose. It is proposed that 'glucose resistance' in central sitesof feeding control may be relevant in the disturbances of energy homeostasis induced by high-fat feeding.Nutrition & Diabetes (2015) 5, e162; doi:10.1038/nutd.2015.12; published online 15 June 2015 (AU)

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