Calabuig-Navarro Virtu, Yamauchi Jun, Lee Sojin, Zhang Ting, Liu Yun-Zi, Sadlek Kelsey, Coudriet Gina M, Piganelli Jon D, Jiang Chun-Lei, Miller Rita, Lowe Mark, Harashima Hideyoshi, Dong H Henry
Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
J Biol Chem. 2015 Jun 19;290(25):15581-15594. doi: 10.1074/jbc.M115.650994. Epub 2015 May 5.
Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice.
内源性葡萄糖生成过多会导致糖尿病患者空腹血糖升高。FoxO6是FoxO亚家族的一个独特成员。为了阐明FoxO6在肝脏糖异生中的作用，并评估其对糖尿病空腹血糖升高发病机制的贡献，我们构建了FoxO6基因敲除（FoxO6-KO）小鼠，然后确定FoxO6功能缺失在生理和病理条件下对肝脏糖异生的影响。FoxO6缺失减弱了FoxO6-KO小鼠的肝脏糖异生并降低了空腹血糖。FoxO6缺陷的原代肝细胞对胰高血糖素反应产生葡萄糖的能力降低。当喂食高脂饮食时，FoxO6-KO小鼠表现出显著增强的葡萄糖耐量和降低的血糖水平，同时胰岛素敏感性提高。这些效应与FoxO6-KO小鼠肝脏糖异生减弱相关。相比之下，野生型同窝小鼠出现脂肪诱导的葡萄糖不耐受，并伴有空腹高胰岛素血症和高血糖的诱导。此外，FoxO6-KO小鼠肝脏和脂肪组织中的巨噬细胞浸润明显减少，这与巨噬细胞C-C趋化因子受体2（CCR2）表达的降低相关，CCR2是调节外周组织中巨噬细胞募集的关键因子。我们的数据表明，FoxO6缺失通过减弱肝脏糖异生和抑制小鼠肝脏及脂肪组织中的巨噬细胞浸润，预防了饮食诱导的葡萄糖不耐受和胰岛素抵抗。
