Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

Tony K.T. Lam, Alessandro Pocai, Roger Gutierrez-Juarez, Silvana Obici, Joseph Bryan, Lydia Aguilar-Bryan, Gary J. Schwartz, Luciano Rossetti

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Abstract

Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic KATP channels or pharmacological blockade (KATP blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.

Original languageEnglish (US)
Pages (from-to)320-327
Number of pages8
JournalNature Medicine
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2005

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lam, T. K. T., Pocai, A., Gutierrez-Juarez, R., Obici, S., Bryan, J., Aguilar-Bryan, L., Schwartz, G. J., & Rossetti, L. (2005). Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nature Medicine, 11(3), 320-327. https://doi.org/10.1038/nm1201