Concerted Action of Aldehyde Dehydrogenases in Depot‐specific Fat Formation

Abstract

Unraveling mechanisms regulating fat distribution in visceral and subcutaneous fat depots is necessary to improve treatments of a number of chronic diseases. Retinoic acid, a transcriptionally active metabolite of vitamin A, plays a key role in differentiation processes. It is produced by the aldehyde dehydrogenase‐1 family of enzymes (aldh1a1,a2,a3). Our objective was to investigate whether differences in RA production by Aldh1, in subcutaneous versus visceral fat, diverge fat formation in these depots.We demonstrated that Aldh1a1 is the major enzyme regulating RA generation in adipocytes in vitro and in vivo. Deficiency in Aldh1a1 inhibits endogenous RA production and suppresses PPARg expression, a key event in 3T3‐L1 adipogenesis, that we rescued by overexpression of Aldh1a1,a3 or both. We identified that visceral fat expressed less Aldh1a2 and a3 than subcutaneous fat in C57/BL6 female mice on regular chow, although Aldh1a1 was predominantly expressed in these depots. Therefore, in Aldh1a1−/− mice, visceral fat essentially lacked all Aldh1 expression, which resulted in 70% decreased expression of PPARg and FABP4 in visceral fat of Aldh1a1−/− vs. WT mice. Consequently, Aldh1a1−/− mice specifically lost visceral fat.Our data suggest that Aldh1 enzymes play a key role in adipogenesis and their concerted action may contribute to differences in fat formation in different depots.