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


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.
Kim
Jane J
JJ
Department of Pediatrics, University of California at San Diego, La Jolla, California, USA. janekim@ucsd.edu
Li
Pingping
P
Huntley
Jessica
J
Chang
Jeffrey P
JP
Arden
Karen C
KC
Olefsky
Jerrold M
JM
D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency*; D017353:Gene Deletion; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*
D004041:Dietary Fats; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones