Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.
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 K(ATP) channels or pharmacological blockade (K(ATP) 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.
Lam
Tony K T
TK
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 701, Bronx, New York 10461, USA.
Pocai
Alessandro
A
Gutierrez-Juarez
Roger
R
Obici
Silvana
S
Bryan
Joseph
J
Aguilar-Bryan
Lydia
L
Schwartz
Gary J
GJ
Rossetti
Luciano
L
D000818:Animals; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004041:Dietary Fats / Q000008:administration & dosage; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology*; D007276:Injections, Intraventricular; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014226:Triazenes / Q000494:pharmacology; D014628:Vagotomy
D004041:Dietary Fats; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D014226:Triazenes; C034613:triacsin C; D005952:Glucose-6-Phosphatase; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat; D005947:Glucose; D005905:Glyburide