Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats
Alessandro Pocai, … , Arduino Arduini, Luciano Rossetti
Alessandro Pocai, … , Arduino Arduini, Luciano Rossetti
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1081-1091. https://doi.org/10.1172/JCI26640.
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Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats

Abstract

Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance.

Authors

Alessandro Pocai, Tony K.T. Lam, Silvana Obici, Roger Gutierrez-Juarez, Evan D. Muse, Arduino Arduini, Luciano Rossetti

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Figure 6

Hypothalamic inhibition of lipid oxidation restores central lipid sensing in OF rats.

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Inhibition of hypothalamic CPT1A expression restrains liver glucose flux...
(A) Experimental protocol. Male Sprague-Dawley rats fed a high-fat diet for 3 days were infused for in the MBH for 6 hours. After 2 hours rats received intravenous saline or a lipid emulsion and [3-3H]-glucose for 4 hours, and a pancreatic basal insulin clamp (1 mU/kg/min) was performed in the final 2 hours. Plasma glucose levels in rats receiving saline, lipid, and CPT1A inhibitor during systemic lipid infusion (LI + CPT). The hyperglycemia induced by a physiologic increase in circulating LCFA levels in OF rats was prevented by the infusion of CPT1A inhibitor. (B) Total LCFA-CoA, linoleyl-CoA, and oleyl-CoA levels in the MBH obtained at the end of the pancreatic insulin clamp. (C) After 3 days’ voluntary overfeeding, LCFAs failed to increase the MBH levels of LCFA-CoAs and to decrease food intake and liver glucose fluxes. The central inhibition of CPT1A restored the regulation of MBH LCFA-CoAs and normalized food intake and liver glucose fluxes. *P < 0.05 CPT1A inhibitor versus control.