Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins.
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.
Lam
Tony K T
TK
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Gutierrez-Juarez
Roger
R
Pocai
Alessandro
A
Bhanot
Sanjay
S
Tso
Patrick
P
Schwartz
Gary J
GJ
Rossetti
Luciano
L
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
D017931:DNA Primers; D007328:Insulin; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D013004:Somatostatin; D013230:Stearoyl-CoA Desaturase; D005947:Glucose; D010072:Oxamic Acid; D019354:Sodium Lactate