Calorie hoarding and thrifting: Foxa3 finds a way

Abstract

Obesity and diabetes are major health concerns worldwide. Western diets, often calorically rich, paired with sedentary habits are driving the current worldwide epidemic of pediatric and adult obesity. In addition, age related energy imbalances lead to increased adiposity and metabolic disorders later in life, making the middle aged population particularly susceptible. Here we discuss how Forkhead box A3 (Foxa3), a family member of the forkhead box binding proteins, can potentially contribute to pathology by playing a double role in metabolism. Recent data revealed that Foxa3 favors the selective expansion of visceral depots under high caloric conditions (e.g., high fat diet) and suppresses subcutaneous fat tissue energy expenditure during aging. This evidence suggests that Foxa3 acts to both preserve and conserve calories, by accumulating fat and by reducing metabolic burn. In other words, Foxa3 appears to function to enable energy “hoarding,” which may be critical for survival of organisms with intermittent exposure to external caloric sources, but pathologic in circumstances where calories are abundant. Understanding how this “calorie hoarder gene” functions may suggest approaches to combat obesity and associated metabolic disorders.

Keywords:

• aging
• Foxa3
• obesity
• PGC1α
• PPARγ
• thrifty

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figure 1. Model proposing the pleiotropic function of Foxa3 on energy conservation, during high fat diet and aging. (A) Foxa3 mRNA levels are selectively increased in visceral fat (Vis fat) in response to high fat diet (HFD) and associated with increased lipid accumulation in the visceral depot and the induction of PPARγ mRNA. (B) Foxa3 levels are primarily elevated in subcutaneous fat depots during the aging process. Schematic representation depicting the competition between Foxa3 and CREB for their binding to regulatory elements at the PGC1α promoter, resulting in the modulation of PGC1α mRNA levels. EE, energy expenditure.

Acknowledgments

We thank Pasha Sarraf for thoughtful discussions.

Funding

This research was supported by funds of the NIDDK Intramural Research Program of the National Institutes of Health.