Journal
DIABETES
Volume 62, Issue 7, Pages 2295-2307Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db12-1629
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [21390067, 24390058, 20790656, 22790875, 23790282, 22126005]
- Specific Research Fund of the National Institutes for Natural Sciences
- Grants-in-Aid for Scientific Research [23790282, 22126005, 20790656, 24390058, 22790875, 21390067, 24590241] Funding Source: KAKEN
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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 melanocordn 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.
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