Concerted Action of Aldehyde Dehydrogenases Influences Depot-Specific Fat Formation

Abstract

Vitamin A metabolite retinoic acid (RA) regulates life-sustaining differentiation processes and metabolic homeostasis. The aldehyde dehydrogenase-1 (Aldh1) family of enzymes (Aldh1a1, a2, and a3) catalyzes RA production from retinaldehyde and thereby controls concentrations of this transcriptionally active metabolite. The hierarchy of Aldh1 functions in adipose tissue has not been elucidated. We hypothesized that Aldh1 enzymes produce endogenous RA and regulate adipogenesis and fat formation in a fat depot-specific manner. We demonstrate that adipogenesis in vitro is accompanied by RA production generated primarily by Aldh1a1. In Aldh1a1-deficient adipocytes, adipogenesis is impaired compared with wild-type adipocytes due to markedly reduced expression of PPARγ regulated through zinc-finger protein 423 (ZFP423)-dependent mechanisms. These effects were recovered to some extent either by RA stimulation or overexpression of any of the Aldh1 enzymes in Aldh1a1(-/-) cells arguing that Aldh1a1 plays a dominant role in autocrine RA production. In vivo studies in C57/BL6 and Aldh1a1(-/-) mice on a regular diet revealed that multiple Aldh1 enzymes regulate differences in the formation of sc and visceral fat. In Aldh1a1(-/-) mice, visceral fat essentially lacked all Aldh1 expression. This loss of RA-producing enzymes was accompanied by 70% decreased expression of ZFP423, PPARγ, and Fabp4 in visceral fat of Aldh1a1(-/-) vs. wild-type mice and by the predominant loss of visceral fat. Subcutaneous fat of Aldh1a1(-/-) mice expressed Aldh1a3 for RA production that was sufficient to maintain expression of ZFP423 and PPARγ and sc fat mass. Our data suggest a paradigm for regulation of fat depots through the concerted action of Aldh1 enzymes that establish RA-dependent tandem regulation of transcription factors ZFP423 and PPARγ in a depot-specific manner.

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

“…These findings are consistent with data from the Aldh1a1 Ϫ/Ϫ mouse model, which demonstrates decreased abdominal fat and body weight (26,37). In addition, we observed increased brown adipose tissue-like conversion of white adipose tissue (defined by increased expression of UCP-1) in animals treated with WIN 18,446 (Fig.…”

Vitamin A supplementation in early life affects later response to an obesogenic diet in rats

“…45 Known RA-mediated transcriptional responses were enhanced in the tissues of RE rats at weaning (day 21), including downregulation of Aldh 1a1 expression in iWAT. 13,49 Downregulation of Aldh 1a1 in the face of upregulation of the RA-degrading enzyme CYP26a1 is suggestive of a homeostatic mechanism to keep constant intracellular RA levels in WAT. The increased cell proliferation potential found in iWAT of young RE-treated rats is in line with repressive effects of RA on the expression of cell cycle breaks (p21 and retinoblastoma protein) previously reported in adipocyte cell models, 50 and with increased thymidine incorporation in cultured adipose precursor cells exposed to RA.…”

“…9,10 Retinoic acid (RA), its acid form, potently blocks adipogenesis of cultured preadipose cells when introduced at early stages of the differentiation process, 11 although other reports indicate that RA at low doses may in fact promote adipogenesis. [12][13][14] Studies in adult rodents treated with RA [15][16][17][18][19][20][21][22][23] or retinaldehyde 24 sustain an antiadiposity action of vitamin A derivatives in vivo. Furthermore, results from animal studies 16,[25][26][27][28] and human observational studies 29,30 point to an inverse relationship between vitamin A status and body fat content.…”

Retinol-Binding Protein 4 and Its Membrane Receptor STRA6 Control Adipogenesis by Regulating Cellular Retinoid Homeostasis and Retinoic Acid Receptor α Activity

“…Although in adipose tissue retinoids regulate a variety of metabolic functions, such as thermogenesis, lipolysis, and fatty acid oxidation (11), a direct action on adipocyte differentiation is likely to contribute to their effects on adiposity (12). Proadipogenic effects of low concentrations of atRA in clonal Ob17 precursor cells, rat preadipocytes, and aldehyde dehydrogenase 1A1 (ALDH1A1)-deficient fibroblasts have been reported (13,14). However, most studies in adipocyte lineage-committed preadipocytes identified atRA as a strong inhibitor of adipogenesis when present at early stages of differentiation (5,(15)(16)(17)(18).…”