Article abstract
Nature Medicine 13, 171 - 180 (2007)
Published online: 4 February 2007 | Corrected online: 18 April 2007 | doi:10.1038/nm1540
Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins
Tony K T Lam1,4,5, Roger Gutierrez-Juarez1,5, Alessandro Pocai1, Sanjay Bhanot2, Patrick Tso3, Gary J Schwartz1 & Luciano Rossetti1
Abstract
Increased production of very low-density lipoprotein (VLDL) is a critical feature of the metabolic syndrome. Here we report that a selective increase in brain glucose lowered circulating triglycerides (TG) through the inhibition of TG-VLDL secretion by the liver. We found that the effect of glucose required its conversion to lactate, leading to activation of ATP-sensitive potassium channels and to decreased hepatic activity of stearoyl-CoA desaturase-1 (SCD1). SCD1 catalyzed the synthesis of oleyl-CoA from stearoyl-CoA. Curtailing the liver activity of SCD1 was sufficient to lower the hepatic levels of oleyl-CoA and to recapitulate the effects of central glucose administration on VLDL secretion. Notably, portal infusion of oleic acid restored hepatic oleyl-CoA to control levels and negated the effects of both central glucose and SCD1 deficiency on TG-VLDL secretion. These central effects of glucose (but not those of lactate) were rapidly lost in diet-induced obesity. These findings indicate that a defect in brain glucose sensing could play a critical role in the etiology of the metabolic syndrome.
- Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
- ISIS Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008, USA
- Department of Pathology, University of Cincinnati, 2120 East Galbraith Road, Cincinnati, Ohio 45237, USA
- Present address: Departments of Physiology and Medicine, University Health Network and University of Toronto, Toronto M5G 1L7, Canada
- These authors contributed equally to this work
Correspondence to: Luciano Rossetti1 e-mail: rossetti@aecom.yu.edu
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