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Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production

Nature Medicine volume 9, pages 756–761 (2003)Cite this article

Abstract

The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo β-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.

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Figure 1: Inhibition of hypothalamic CPT1.
Figure 2: Genetic or pharmacological inhibition of CPT1 in ARC reduced CPT1 activity and increased LCFA-CoA.
Figure 3: Inhibition of hypothalamic CPT1L by genetic or pharmacological means decreased food intake.
Figure 4: Inhibition of hypothalamic CPT1 improved hepatic but not peripheral insulin action.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (to L.R.; DK48321 and DK45024) and from the Albert Einstein College of Medicine Diabetes Research & Training Center. S.O. was the recipient of a post-doctoral fellowship and a Junior Faculty Award from the American Diabetes Association.

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Author notes

  1. Arduino Arduini

    Present address: Pharmaceutical Division, Vascular & Metabolic Diseases, F. Hoffmann-La Roche Ltd., CH-4070, Basel, Switzerland

Authors and Affiliations

  1. Departments of Medicine and Molecular Pharmacology, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Silvana Obici, Zhaohui Feng & Luciano Rossetti

  2. Department of Metabolism & Endocrinology, Sigma Tau Pharmaceutical Industries, Via Pontina km 30,400, Pomezia, 00040, Italy

    Arduino Arduini & Roberto Conti

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Correspondence to Luciano Rossetti.

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Competing interests

A.A. and R.C. are employed by a drug company and they may have interest in the development of ST1326 as a potential treatment for diabetes or obesity.

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Obici, S., Feng, Z., Arduini, A. et al. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9, 756–761 (2003). https://doi.org/10.1038/nm873

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