Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
- Chitoku Toda1,
- Tetsuya Shiuchi2,
- Haruaki Kageyama3,4,
- Shiki Okamoto1,5,
- Eulalia A. Coutinho1,5,
- Tatsuya Sato1,5,
- Yuko Okamatsu-Ogura6,
- Shigefumi Yokota1,5,
- Kazuyo Takagi1,5,
- Lijun Tang1,5,
- Kumiko Saito1,
- Seiji Shioda3 and
- Yasuhiko Minokoshi1,5⇑
- 1Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan
- 2Department of Integrative Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
- 3Department of Anatomy, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
- 4Faculty of Health Care, Kiryu University, Midori, Gunma, Japan
- 5Department of Physiological Sciences, Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa, Japan
- 6Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Corresponding author: Yasuhiko Minokoshi, .
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 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 the MEK-ERK pathway in the VMH by leptin may play a 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1629/-/DC1.
- Received November 24, 2012.
- Accepted March 16, 2013.
- © 2013 by the American Diabetes Association.
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