Hypothalamic leucine metabolism regulates liver glucose production

Ya Su, Tony K T Lam, Wu He, Alessandro Pocai, Joseph Bryan, Lydia Aguilar-Bryan, Roger Gutiérrez-Juárez

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Amino acids profoundly affect insulin action and glucose metabolism in mammals. Here, we investigated the role of the mediobasal hypothalamus (MBH), a key center involved in nutrient-dependent metabolic regulation. Specifically, we tested the novel hypothesis that the metabolism of leucine within the MBH couples the central sensing of leucine with the control of glucose production by the liver. We performed either central (MBH) or systemic infusions of leucine in Sprague-Dawley male rats during basal pancreatic insulin clamps in combination with various pharmacological and molecular interventions designed to modulate leucine metabolism in the MBH. We also examined the role of hypothalamic ATP-sensitive K + channels (K ATP channels) in the effects of leucine. Enhancing the metabolism of leucine acutely in the MBH lowered blood glucose through a biochemical network that was insensitive to rapamycin but strictly dependent on the hypothalamic metabolism of leucine to α-ketoisocaproic acid and, further, insensitive to acetyl- and malonyl-CoA. Functional K ATPchannels were also required. Importantly, molecular attenuation of this central sensing mechanism in rats conferred susceptibility to developing hyperglycemia. We postulate that the metabolic sensing of leucine in the MBH is a previously unrecognized mechanism for the regulation of hepatic glucose production required to maintain glucose homeostasis.

Original languageEnglish (US)
Pages (from-to)85-93
Number of pages9
JournalDiabetes
Volume61
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Leucine
Hypothalamus
Glucose
Liver
Adenosine Triphosphate
Insulin
Malonyl Coenzyme A
Acetyl Coenzyme A
Sirolimus
Hyperglycemia
Sprague Dawley Rats
Blood Glucose
Mammals
Homeostasis
Pharmacology
Amino Acids
Food
Acids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Su, Y., Lam, T. K. T., He, W., Pocai, A., Bryan, J., Aguilar-Bryan, L., & Gutiérrez-Juárez, R. (2012). Hypothalamic leucine metabolism regulates liver glucose production. Diabetes, 61(1), 85-93. https://doi.org/10.2337/db11-0857

Hypothalamic leucine metabolism regulates liver glucose production. / Su, Ya; Lam, Tony K T; He, Wu; Pocai, Alessandro; Bryan, Joseph; Aguilar-Bryan, Lydia; Gutiérrez-Juárez, Roger.

In: Diabetes, Vol. 61, No. 1, 01.2012, p. 85-93.

Research output: Contribution to journalArticle

Su, Y, Lam, TKT, He, W, Pocai, A, Bryan, J, Aguilar-Bryan, L & Gutiérrez-Juárez, R 2012, 'Hypothalamic leucine metabolism regulates liver glucose production', Diabetes, vol. 61, no. 1, pp. 85-93. https://doi.org/10.2337/db11-0857
Su Y, Lam TKT, He W, Pocai A, Bryan J, Aguilar-Bryan L et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes. 2012 Jan;61(1):85-93. https://doi.org/10.2337/db11-0857
Su, Ya ; Lam, Tony K T ; He, Wu ; Pocai, Alessandro ; Bryan, Joseph ; Aguilar-Bryan, Lydia ; Gutiérrez-Juárez, Roger. / Hypothalamic leucine metabolism regulates liver glucose production. In: Diabetes. 2012 ; Vol. 61, No. 1. pp. 85-93.
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