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

Abstract

Aging is associated with increased adiposity and diminished thermogenesis, but the critical transcription factors influencing these metabolic changes late in life are poorly understood. We recently demonstrated that the winged helix factor forkhead box protein A3 (Foxa3) regulates the expansion of visceral adipose tissue in high-fat diet regimens; however, whether Foxa3 also contributes to the increase in adiposity and the decrease in brown fat activity observed during the normal aging process is currently unknown. Here we report that during aging, levels of Foxa3 are significantly and selectively up-regulated in brown and inguinal white fat depots, and that midage Foxa3-null mice have increased white fat browning and thermogenic capacity, decreased adipose tissue expansion, improved insulin sensitivity, and increased longevity. Foxa3 gain-of-function and loss-of-function studies in inguinal adipose depots demonstrated a cell-autonomous function for Foxa3 in white fat tissue browning. Furthermore, our analysis revealed that the mechanisms of Foxa3 modulation of brown fat gene programs involve the suppression of peroxisome proliferator activated receptor γ coactivtor 1 α (PGC1α) levels through interference with cAMP responsive element binding protein 1-mediated transcriptional regulation of the PGC1α promoter. Overall, our data demonstrate a role for Foxa3 in energy expenditure and in age-associated metabolic disorders.obesity | diabetes

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

“…Given that GCs previously have been reported to affect food intake in rodents (21, 22), we pair-fed the mice to exclude any confounding effects caused by the potential influence of GC on caloric intake. As previously described, 2-mo-old WT and Foxa3-null mice on a normal chow diet before treatment had comparable body weight, fat mass, and lean mass (29). Analysis of these metabolic parameters in mice after Dex treatment revealed that ablation of Foxa3 gave protection from the Dex-induced increase in fat mass and adipose tissue weight (Fig.…”

“…WT and Foxa3-null mice (29) were kept in a humidity-and temperature-controlled environment on a 12-h light/dark cycle, with free access to chow diet and water. Mouse experiments were performed according to guidelines of the National Institute of Diabetes and Digestive and Kidney Diseases Animal Care and Use Committee and approved by the Institutional Animal Care and Use Committee of the National Institute of Diabetes and Digestive and Kidney Diseases.…”

“…Among them, members of the Foxa subfamily play important roles in early organ development and metabolism (24,25). We recently have shown that Forkhead box protein A3 (Foxa3), previously known to play a role in liver during long-term starvation and in pancreas development (26,27), is involved in the selective expansion of epididymal fat depots during a high-fat diet and in the suppression of energy expenditure during aging (28,29) and that its variants are associated with human metabolic traits (30). Our studies also have revealed that Foxa3 levels are inducible in visceral fat in Significance This paper shows a previously unidentifed relationship between the transcription factor forkhead box a3 (Foxa3) and the glucocorticoid receptor (GR) by demonstrating, for the first time to our knowledge, that Foxa3 is a target of GR and that it is required for GR transcriptional function in fat depots.…”

“…response to a high-fat diet and in s.c. adipose tissue (iWAT) and BAT during aging (28,29); however, the identity of the critical upstream regulators that control Foxa3 expression is currently unknown. Given the longstanding evidence that GC levels and signaling increase during nutritional overload and in the aging process and that long-term GC treatment leads to increased visceral adiposity and reduced thermogenesis, we explored the possible existence of a connection between GC and Foxa3.…”

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

“…Intriguingly, we found differential methylation in Irs2 and Foxa 3, both of which are involved in insulin sensitivity (Ma et al ., 2014). While we see an increase in their expression in unexposed old animals, we do not see this increase in 6‐month‐old exposed animals.…”