| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Research Abstract |
Recent studies have revealed that insulin signaling in pancreatic b cells and hypothalamus are critical for the maintenance of nutrient and energy homeostasis, the failure of which are hallmark of metabolic syndrome. We previously reported that forkhead transcription factor FoxO1, a downstream effector of insulin signaling, plays important roles in b cells and hypothalamus. However, in those studies we investigated the roles of FoxO1independently in either pancreas or hypothalamus. Therefore, to determine combined implications of FoxO1 in hypothalamus and pancreas in the development of metabolic syndrome, we generated constitutively active (CA) FoxO1 knock-in mice (KI), in which CA-FoxO1 is expressed in both hypothalamus and pancreas. Here we show that KI mice develop obesity and glucose intolerance due to increased food intake, decreased energy expenditure and impaired insulin secretion. We also show that KI mice have increased hypothalamic Agrp and Npy expressions and decreased UCP1 and PGC1a expressions in adipose tissues and skeletal muscle. Impaired insulin secretion is associated with decreased expressions of Pdx1, MafA and NeuroD in islets, although b cell mass is paradoxically increased in KI mice. Taken together, we propose that uncontrolled FoxO1 activation in hypothalamus and pancreas could account for the development of metabolic syndrome.
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