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

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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Correspondence to Luciano Rossetti.

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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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