Kim Jane J, Li Pingping, Huntley Jessica, Chang Jeffrey P, Arden Karen C, Olefsky Jerrold M
Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.
Diabetes. 2009 Jun;58(6):1275-82. doi: 10.2337/db08-1001. Epub 2009 Mar 16.
Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.
In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet-induced obesity and adipose tissue metabolism.
We showed that reduced FoxO1 expression protects mice against obesity-related insulin resistance with marked improvement not only in hepatic insulin sensitivity but also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism. Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.
These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPARgamma function.
叉头框O（FoxO）转录因子是胰岛素信号通路在进化上保守的靶点，可根据营养物质供应的变化调节新陈代谢和细胞分化。虽然已知FoxO1亚型在脂肪生成中起关键作用，但其在分化的脂肪组织中的生理作用仍不清楚。
在本研究中，我们分析了FoxO1单倍体不足小鼠的表型，以研究FoxO1在高脂饮食诱导的肥胖和脂肪组织代谢中的作用。
我们发现，FoxO1表达降低可保护小鼠免受肥胖相关的胰岛素抵抗，不仅肝脏胰岛素敏感性显著改善，骨骼肌胰岛素作用也明显增强。FoxO1单倍体不足还导致脂肪组织中过氧化物酶体增殖物激活受体（PPAR）γ基因表达增加，已知影响代谢的PPARγ靶基因表达增强。此外，用PPARγ激动剂罗格列酮治疗小鼠，可使FoxO1单倍体不足动物的体内胰岛素敏感性得到更大改善，包括循环促炎细胞因子减少。
这些发现表明，FoxO1蛋白对胰岛素作用起负调节作用，其作用至少部分可通过抑制PPARγ功能来解释。
