Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 4, Pages 1081-1091Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI26640
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Funding
- NIA NIH HHS [T32-AG023475, T32 AG023475, AG 21654, P01 AG021654] Funding Source: Medline
- NIDDK NIH HHS [DK 20541, P60 DK020541, DK 48321, DK 45024, P30 DK020541, R01 DK048321, R37 DK048321, R01 DK045024] Funding Source: Medline
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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.
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