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Nutr Diabetes
2015 Jun 15;5:e162. doi: 10.1038/nutd.2015.12.
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Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis.
de Andrade IS
,
Zemdegs JC
,
de Souza AP
,
Watanabe RL
,
Telles MM
,
Nascimento CM
,
Oyama LM
,
Ribeiro EB
.
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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 at evaluating whether obesity induced by chronic high-fat intake affects the ability of hypothalamic glucose to control feeding. We hypothesized 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 was measured after intracerebroventricular (i.c.v.) glucose. Glycemia and glucose content of medial hypothalamus microdialysates were measured in response to interperitoneal (i.p.) glucose or meal intake after an overnight fast. The effect of refeeding on whole hypothalamus levels of glucose transporter proteins (GLUT) 1, 2 and 4, AMPK and phosphorylated AMPK levels was determined by immunoblotting.
RESULTS: High-fat rats had higher body weight and fat content and serum leptin than control rats, but normal insulin levels and glucose tolerance. I.c.v. glucose inhibited food intake in control but failed to do so in high-fat rats. Either i.p. glucose or refeeding significantly increased glucose hypothalamic microdialysate levels in the control rats. These levels showed exacerbated increases in the high-fat rats. GLUT1 and 4 levels were not affected by refeeding. GLUT2 levels decreased and phosphor-AMPK levels increased in the high-fat rats but not in the controls.
CONCLUSIONS: The findings suggest that, in the high-fat rats, a defective glucose sensing by decreased GLUT2 levels contributed to an inappropriate activation of AMPK after refeeding, despite increased extracellular glucose levels. These derangements were probably involved in the abolition of hypophagia in response to i.c.v. glucose. It is proposed that ''glucose resistance'' in central sites of feeding control may be relevant in the disturbances of energy homeostasis induced by high-fat feeding.
Figure 5. Hypothalamic protein levels of AMPK (a) and pAMPK (b) in control and high-fat groups either in the fasted state or after refeeding. n=4–5 animals *P<0.05 vs the respective fasted group.
Figure 6. Diagram depicting the responses induced by refeeding in control lean and in dietary obese rats. In lean rats, food-derived glucose reaching the hypothalamus is sensed by GLUT2, leading to decreased AMPK and feeding inhibition. This mechanism is disrupted in the obese rats. Although the feeding-induced hypothalamic glucose levels are in excess, the decreased GLUT2 levels impair glucose sensing, leading to inappropriate AMPK increase and abolition of hypophagia.
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