Date : 04.19.2013

Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle.

Category : Research Topic
 Division of Endocrinology and Metabolism,NIPS
 

Abstract

Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal–regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not that of the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of MEK-ERK pathway in the VMH by leptin may play an role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus, and leading to an increase in insulin sensitivity in red-type muscle.

Figure Model for the mechanism of regulation of glucose metabolism in muscle and liver by leptin in the VMH.

minokoshi-houkokuENG.jpg

Leptin receptor (Ob-Rb) in the VMH plays a key role in the regulation of glucose metabolism and insulin sensitivity in muscle and liver by leptin. Leptin-activated ERK1/2 signaling in the VMH increases insulin sensitivity and glucose utilization in red muscle through activation of melanocortin receptor (MCR) in the VMH. Ob-Rb–expressing VMH neurons likely activate POMC neurons either in the ARC (arcuate nucleus of the hypothalamus) itself or at their synaptic connections with VMH neurons through the ERK1/2 pathway. The ERK1/2 pathway then stimulates synaptic plasticity for POMC neurons and MCR-expressing neurons in the VMH. Whereas other brain sites may contribute to the leptin-induced enhancement of the suppressive effect of insulin on hepatic glucose production, leptin-activated STAT3 signaling in the VMH mediates this enhancement by inhibiting glycogen phosphorylase a activity in liver. 3V, third ventricle.
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Published Paper

Extracellular Signal-Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle.

Toda C, Shiuchi T, Kageyama H, Okamoto S, Coutinho EA, Sato T, Okamatsu-Ogura Y, Yokota S, Takagi K, Tang L, Saito K, Shioda S, Minokoshi Y.

Diabetes 2013
published online in
http://diabetes.diabetesjournals.org/content/early/2013/03/22/db12-1629.long
before print March 25, 2013
doi: 10.2337/db12-1629

This work was collaborated with Showa University, Hokkaido University, and Kiryu University.