Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle.

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 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.

• Authors: Chitoku Toda, Tetsuya Shiuchi, Haruaki Kageyama, Shiki Okamoto, Eulalia A Coutinho, Tatsuya Sato, Yuko Okamatsu-Ogura, Shigefumi Yokota, Kazuyo Takagi, Lijun Tang, Kumiko Saito, Seiji Shioda, Yasuhiko Minokoshi
• Journal: Diabetes (Diabetes) Vol. 62 Issue 7 Pg. 2295-307 (Jul 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23530005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Chromones
• Enzyme Inhibitors
• Insulin
• Leptin
• Morpholines
• Nitriles
• Receptors, Corticotropin
• U 0126
• SHU 9119
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Melanocyte-Stimulating Hormones
• Extracellular Signal-Regulated MAP Kinases
• Glucose

Topics

• Animals
• Body Weight (drug effects)
• Butadienes (pharmacology)
• Chromones (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Glucose (metabolism)
• Insulin (pharmacology)
• Leptin (pharmacology)
• Male
• Melanocyte-Stimulating Hormones (pharmacology)
• Mice
• Morpholines (pharmacology)
• Muscle, Skeletal (drug effects, metabolism)
• Nitriles (pharmacology)
• Phosphorylation (drug effects)
• Receptors, Corticotropin (antagonists & inhibitors)
• Signal Transduction (drug effects, physiology)
• Ventromedial Hypothalamic Nucleus (drug effects, metabolism)