Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins Tony K T Lam 1,4,5 , Roger Gutierrez-Juarez 1,5 , Alessandro Pocai 1 , Sanjay Bhanot 2 , Patrick Tso 3 , Gary J Schwartz 1 & Luciano Rossetti 1 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. A cluster of metabolic risk factors confers susceptibility to type 2 diabetes and cardiovascular disease 1–8 . The increased secretion of very low-density lipoprotein (VLDL) by the liver is a key component of this metabolic syndrome 1,2 . The biosynthesis and secretion of triglyceride- rich lipoproteins by the liver is a multistep process that is finely regulated by metabolic and endocrine factors 3,6,7,9,10 . Substrate avail- ability and insulin are particularly important for determining the rate of secretion of VLDL-triglyceride 9 by affecting the regulation of hepatic triglyceride and cholesterol synthesis, and that of the forma- tion and maturation of secreted lipoproteins 3,6,7,10–12 . Apolipoprotein B (ApoB) is an essential component of liver-derived VLDL and provides the protein core for the nascent VLDL particle. During the assembly of nascent VLDL particles with triglyceride droplets, ApoB–containing pre-VLDL particles are assembled within the lumen of the rough endoplasmic reticulum through a process partly catalyzed by the microsomal triglyceride transfer protein (MTP) 11,12 . MTP also plays a critical role in the formation of lipid droplets in the smooth endoplasmic reticulum 11 . The addition of bulk lipids to the nascent VLDL particle involves the fusion of lipid droplets with pre-VLDL particles and can be stimulated by the availability of the monounsaturated fatty acid oleic acid 10 . Diets rich in fat and carbohydrates have a profound effect on circulating levels of triglycer- ide and on VLDL secretion 6,13–15 . During the last several years, we and others have provided experi- mental evidence supporting the notion that the availability of nutri- ents regulates the activity of hypothalamic neuronal pathways designed to couple energy needs with nutrient intake and endogenous nutrient output 8,16–18 . These central pathways are prone to faltering in the presence of prolonged overfeeding 18–20 . Brain glucose sensing has been implicated in the regulation of food intake 21,22 , hypoglycemia counter-regulation 23,24 and liver glucose homeostasis 25 . Here we tested the hypothesis that the central metabolism of glucose to pyruvate also controls the rate of TG-VLDL secretion by the liver (Fig. 1a). RESULTS Brain glucose metabolism and lipid homeostasis To examine the central effects of glucose on lipid homeostasis, we infused glucose or mannitol (2 mM) into the third cerebral ventricle of conscious rats. The intracerebroventricular (i.c.v.) glucose admin- istration increased hypothalamic glucose concentration by B70%, a level observed when there is an B2-fold increase in normal peripheral glucose levels (Supplementary Fig. 1 online). Glucose i.c.v. did not modify the levels of plasma fatty acids (Fig. 1b) but markedly decreased the circulating levels of triglycerides (Fig. 1b). Because changes in circulating insulin levels can modulate triglyceride meta- bolism 9 , we also examined the effect of central glucose on plasma triglyceride levels in the presence of fixed and basal insulin concentra- tions (pancreatic basal insulin clamp; Supplementary Table 1 online). Glucose i.c.v. similarly suppressed plasma triglyceride levels during pancreatic clamp experiments (Fig. 1b). Glucose can generate up to two molecules of lactate in astrocytes. On the basis of the astrocyte-neuron lactate shuttle hypothesis, extracellular lactate can then be used by neurons for the formation of pyruvate (ref. 26 and Fig. 1a). Because the effects of central glucose © 2007 Nature Publishing Group http://www.nature.com/naturemedicine Received 20 October 2006; accepted 21 December 2006; published online 4 February 2007; corrected online 18 April 2007; doi:10.1038/nm1540 1 Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. 2 ISIS Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008, USA. 3 Department of Pathology, University of Cincinnati, 2120 East Galbraith Road, Cincinnati, Ohio 45237, USA. 4 Present address: Departments of Physiology and Medicine, University Health Network and University of Toronto, Toronto M5G 1L7, Canada. 5 These authors contributed equally to this work. Correspondence should be addressed to L.R. (rossetti@aecom.yu.edu). NATURE MEDICINE VOLUME 13 [ NUMBER 2 [ FEBRUARY 2007 171 ARTICLES