title: Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins.
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.
authors.affiliation: Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
authors.forename: Roger
authors.initials: R
authors.lastname: Gutierrez-Juarez
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Patrick
authors.initials: P
authors.lastname: Tso
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Luciano
authors.initials: L
authors.lastname: Rossetti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010072:Oxamic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019354:Sodium Lactate / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D017931:DNA Primers; D007328:Insulin; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D013004:Somatostatin; D013230:Stearoyl-CoA Desaturase; D005947:Glucose; D010072:Oxamic Acid; D019354:Sodium Lactate