| Project/Area Number |
16390062
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental physiology (including Physical medicine and Nutritional physiology)
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| Research Institution | National Institute for Physiological Sciences |
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Principal Investigator |
MINOKOSHI Yasuhiko National Institute for Physiological Sciences, Department of Developmental Physiology, Professor, 発達生理学研究系, 教授 (10200099)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Shiki National Institute for Physiological Sciences, Department of Developmental Physiology, Assistant Professor, 発達生理学研究系, 助教 (40342919)
SHIUCHI Tetsuya National Institute for Physiological Sciences, Department of Developmental Physiology, Assistant Professor, 発達生理学研究系, 助教 (70372729)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2005: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | feeding behavior / AMP kinase / hypothalamus / leptin / obesity / metabolic syndrome / 国際情報交換 / アメリカ合衆国:フランス |
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| Research Abstract |
AMP kinase (AMPK) is a metabolic sensor that regulates energy metabolism. We have previously shown that leptin stimulates fatty acid oxidation in skeletal muscle via AMPK. AMPK is widely expressed-locations include neurons and glial cells. We hypothesized that hypothalamic AMPK might mediate hormonal and nutrient effects on food intake and energy balance.
Many anorexigens including leptin suppressed α2 AMPK activity in the arcuate (ARH) and paraventricular (PVH) hypothalamus in mice, while many orexigens including AGRP increased α2 AMPK activity in the hypothalamic nucleus. Expression of constitutively active (CA)-AMPK and dominant negative (DN)-AMPK in the medial hypothalamus reciprocally regulated food intake and body weight, and CA-AMPK in the medial hypothalamus inhibited leptin-induced anorexia. Moreover, chronic expression of CA-AMPK in the PVH also increased food intake, then causing massive obesity.
We further examined the molecular mechanism of leptin-induced fatty acid oxidation in skeletal muscle cells, using C2C12 cells. Leptin stimulated fatty acid oxidation and a2 AMPK activity in C2C12 cells. Leptin-induced fatty acid oxidation is abolished by siRNA of α2 AMPK. Furthermore, we found that α2β2γ1 AMPK translocated to the nucleus and stimulated PPARa gene expression in response to leptin, while α2β1γ1AMPK retained in the cytoplasm and phosphorylated acetyl-CoA carboxylase, where it induced fatty acid oxidation in mitochondria. Our studies identified that nuclear translocation of α2β2γ1AMPK is mediated by the nuclear localization signal in the a2 subunit, and myristoylation of β1 retains the a2AMPK to the mitochondrial membrane and stimulates fatty acid oxidation. Thus, leptin-AMPK system plays a crucial role in the control of food intake and fatty acid metabolism.
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