PDK1 deficiency in POMC-Expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response
PDK1 deficiency in POMC-Expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response
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DOI：
10.1016/j.cmet.2008.01.006
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发表时间：
2008-04-01
期刊：
影响因子：
29
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
--
作者：
Belgardt, Bengt F.;Husch, Andreas;Bruening, Jens C.
胰岛素和瘦素刺激的磷脂酰肌醇 3 激酶 (PI3K) 激活已被证明在能量稳态的中央控制中发挥着关键作用。为了描述 PI3K 下游通路在阿片黑皮素原 (POMC) 细胞调节中的重要性，我们培育了在 POMC 表达细胞中选择性失活 3-磷酸肌醇依赖性蛋白激酶 1 (PDK1) 的小鼠（PDK1(Delta POMC) 小鼠）。 PDK1(Delta POMC)小鼠最初表现出食欲亢进、体重增加以及下丘脑 POMC 表达减少导致的葡萄糖代谢受损。另一方面，PDK1（Delta POMC）小鼠表现出进行性、严重的皮质醇功能减退症，这是由于垂体中表达 POW 的促肾上腺皮质激素的丧失所致。 FOXO1 显性失活突变体在 POW 细胞中的表达足以改善 PDK1(Delta POMC) 小鼠的正能量平衡，但不能恢复正常的垂体功能。这些结果揭示了下丘脑和垂体 POMC 细胞中 PDK1 信号在控制能量稳态和应激反应中的重要但不同的作用。
Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(Delta POMC) mice). PDK1(Delta POMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(Delta POMC) mice exhibit progressive, severe hypocortisolism caused by loss of POW-expressing corti-cotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POW cells is sufficient to ameliorate positive energy balance in PDK1(Delta POMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.