title: 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.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
authors.forename: Chitoku
authors.initials: C
authors.lastname: Toda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.forename: Haruaki
authors.initials: H
authors.lastname: Kageyama
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.forename: Eulalia A
authors.initials: EA
authors.lastname: Coutinho
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okamatsu-Ogura
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yokota
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takagi
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.forename: Kumiko
authors.initials: K
authors.lastname: Saito
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D009025:Morpholines; D009570:Nitriles; D018043:Receptors, Corticotropin; C113580:U 0126; C103272:SHU 9119; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D009074:Melanocyte-Stimulating Hormones; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose