Nature Medicine11, 320 - 327 (2005)
Published online: 27 February 2005; | doi:10.1038/nm1201
Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis
Tony K T Lam1, Alessandro Pocai1, Roger Gutierrez-Juarez1, Silvana Obici1, Joseph Bryan2, Lydia Aguilar-Bryan2, Gary J Schwartz1
& Luciano Rossetti1
1
Departments of Medicine, Neuroscience, & Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 701, Bronx, New York 10461, USA.
2
Departments of Medicine and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Room 700 BF, Houston, Texas 77030, USA.
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.
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