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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Research Article Metabolism

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 5

Inhibition of hypothalamic CPT1A expression restrains liver glucose fluxes in OF rats.

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Hypothalamic inhibition of lipid oxidation restores central lipid sensin...
(A) On day 0, icv cannulae were surgically implanted. Arterial and venous catheters were placed on day 14, and icv injections of CPT1A-Ribo or control vector were performed on day 19 following 2 days of overfeeding. Clamp studies were performed on day 21. Rats receiving vector as control were pair-fed to the level of CPT1A-Ribo. (B) Pancreatic insulin clamp procedure. (C) Glucose infusion rate during the clamp in SC or OF rats. (D) Inhibition of glucose production during the clamp period expressed as percent decrease from basal glucose production. CPT1A-Ribo markedly reduced the flux through G6Pase (E) and gluconeogenesis (F) and suppressed G6pc (G) and Pck1 (H) gene expression in SC and OF rats. *P < 0.05 versus control.