We all know how it feels to have overindulged at dinner. That bloated feeling is the result of ignoring signals from a complex pathway that has the hypothalamus — which senses the availability of circulating nutrients — at its centre. By focusing on the lipid metabolism branch of this regulatory network, Silvana Obici and colleagues have shown that carnitine palmitoyltransferase-1 (CPT1) has a crucial role in the control of food intake and endogenous glucose production.
In a study published in Nature Medicine, Obici et al. selectively reduced lipid oxidation in the hypothalamus by decreasing the activity of CPT1, an enzyme that regulates the entry of long-chain fatty acids (LCFAs) into mitochondria. The authors used intracerebroventricular infusion of a CPT1-specific ribozyme or pharmacological inhibitors to reduce CPT1 activity — and consequently increase the hypothalamic concentration of LCFAs — in the arcuate nuclei of rats. The result was a 50% reduction in voluntary food intake, an effect that lasted at least 48 hours after a single dose of ribozyme or inhibitor.
To assess the impact of CPT1 inhibition on glucose homeostasis, the rate of glucose infusion required to prevent hypoglycaemia in CPT1-inhibited rats was measured while maintaining the peripheral insulin concentration at a fixed basal level. Inhibition of CPT1 necessitated a rate of glucose administration that was up to fivefold greater than in untreated controls. The authors showed that suppression of endogenous glucose production — not stimulation of glucose uptake — accounted for this excessive requirement for exogenous glucose.
These data show that the build-up of LCFAs in a population of hypothalamic neurons due to the inhibition of CPT1 represents a central signal of 'nutrient abundance' that feeds back to limit glucose production. Manipulation of fatty acid oxidation therefore warrants further investigation as a potential target for the treatment of metabolic disorders such as obesity and type 2 diabetes.
ORIGINAL RESEARCH PAPER
Obici, S. et al. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Med. 9, 756–761 (2003)
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Farley, S. Buffet belly. Nat Rev Neurosci 4, 521 (2003). https://doi.org/10.1038/nrn1170
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DOI: https://doi.org/10.1038/nrn1170