FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue.

ABSTRACT:

Objective

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.

Research design and methods

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.

Results

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.

Conclusions

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.

SUBMITTER: Kim JJ 

PROVIDER: S-EPMC2682681 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature