Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Endocrinology. 2012 Feb;153(2):659-71. doi: 10.1210/en.2011-1635. Epub 2011 Dec 20.
Recent studies have revealed that insulin signaling in pancreatic β-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in β-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although β-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.
最近的研究表明，胰岛素信号在胰腺β细胞和下丘脑对于维持营养和能量平衡至关重要，而这种平衡的失败是代谢综合征的标志。我们之前曾报道，叉头转录因子家族 O 亚家族包含蛋白的 FoxO1（FoxO1）是胰岛素信号的下游效应物，当我们独立研究 FoxO1 在胰腺和下丘脑中的作用时，它在β细胞和下丘脑中发挥着重要作用。然而，由于代谢综合征是由下丘脑和胰腺的联合紊乱引起的，为了阐明 FoxO1 在这些器官中的联合影响，我们生成了在下丘脑和胰腺中都具有特异性激活的组成型活性 FoxO1 敲入（KI）小鼠。由于进食增加、能量消耗减少和胰岛素分泌受损，KI 小鼠发展为肥胖、胰岛素抵抗、葡萄糖不耐受和高甘油三酯血症，这些都是代谢综合征的特征。KI 小鼠还增加了下丘脑的 Agouti 相关蛋白和神经肽 Y 水平，降低了脂肪组织和骨骼肌中的解偶联蛋白 1 和过氧化物酶体增殖物激活受体 γ 共激活因子 1α 水平。胰岛素分泌受损与胰腺和十二指肠同源盒 1（Pdx1）、肌醇多磷酸神经酰胺酶相关纤维肉瘤癌基因同源物 A（MafA）和神经发生分化 1（NeuroD）在胰岛中的表达减少有关，尽管 KI 小鼠的β细胞质量反而增加。基于这些结果，我们提出，下丘脑和胰腺中不受控制的 FoxO1 激活是肥胖和葡萄糖不耐受发展的原因，而肥胖和葡萄糖不耐受是代谢综合征的标志。
