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Significance This paper reports that the transcription factor forkhead box protein A3 (Foxa3) is directly involved in the development of age-associated obesity and insulin resistance. Mice that lack the Foxa3 gene remodel their fat tissues, store less fat, and burn more energy as they age. These mice also live significantly longer. We show that Foxa3 suppresses a key metabolic cofactor, PGC1α, which is involved in the gene programs that turn on energy expenditure in adipose tissues. Overall, these findings suggest that Foxa3 contributes to the increased adiposity observed during aging, and that it can be a possible target for the treatment of metabolic disorders.

Role of forkhead box protein A3 in age-associated metabolic decline