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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We wish to thank B. Liu, J. Liu, C. Baveghems and S. Gaweda for technical assistance. This work was supported by grants from the US National Institutes of Health (to L. Rossetti, DK 45024, DK 48321 and AG 21654; to G. J. Schwartz, DK 47208; to J. Bryan, DK52771; to L. Aguilar-Bryan, DK57671), from the Albert Einstein College of Medicine Diabetes Research & Training Center (DK 20541). S. Obici is the recipient of a Junior Faculty Award from the American Diabetes Association. T.K.T. Lam is supported by a Training Grant from the National Institute of Aging (T32-AG023475).
The authors declare no competing financial interests.
Tracer verification of the placement of hypothalamic cannulae. (PDF 15 kb)
Hypothalamic expression of SUR1. (PDF 19 kb)
Pivotal role of efferent vagal input to the liver in modulating glucose kinetics. (PDF 69 kb)
Increased lipid availability rapidly induces hyperglycemia in overfed rats. (PDF 22 kb)
Characteristics of the experimental groups before, during and after the pancreatic clamp glibenclamide studies (PDF 25 kb)
Glibenclamide studies: specific activities of hepatic substrates used to calculate the direct pathway and the indirect pathway in rats receiving systemic lipid infusions (PDF 22 kb)
Characteristics of the Sur1 knockout (Sur1KO) vs. WT mice before and during the lipid pancreatic clamp studies (PDF 20 kb)
Characteristics of the experimental groups before, during and after the pancreatic clamp hepatic vagotomy studies (PDF 25 kb)
Hepatic vagotomy studies: specific activities of hepativ substrates used to calculate the direct pathway nd the indirect pathway in rats receiving systemic lipid infusions (PDF 21 kb)
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Lam, T., Pocai, A., Gutierrez-Juarez, R. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11, 320–327 (2005). https://doi.org/10.1038/nm1201
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