Retinaldehyde‐Mediated Lipolysis Underlay Sexual Dimorphism in Visceral Obesity in Mice

Increased risk of mortality in men and women is associated with the development of visceral fat that occurs in a sex‐specific manner by poorly understood mechanisms. Vitamin A metabolites: retinaldehyde (Rald) and retinoic acid (RA) are known to regulate key biological processes. Here, we explored the role of Rald and RA in sex‐specific fat formation, in a mouse model deficient in Aldh1a1, a major RA‐producing enzyme in white adipose tissue. The Aldh1a1 −/− mice displayed a lean phenotype compared to wild type (WT), even on a high‐fat (HF) diet (300days). While subcutaneous fat remained similar in WT males and females, it was reduced in the Aldh1a1 −/− mice. Strikingly, only Aldh1a1 −/− females had significant reduction in visceral fat mass (12.3‐fold lower than WT females), while visceral fat reduction in Aldh1a1 −/− males was insignificant (2.3‐fold) compared to WT males. We found markedly higher protein levels (compared to WT) of adipose triglyceride lipase (Atgl) in Aldh1a1 −/− females vs. males. Consistant with Atgl's key role in lipolysis, visceral fat in Aldh1a1 −/− female, but not male mice has Atgl‐positive staining in clusters of multilocular cells, also co‐expressing thermogenic proteins. The effective induction of Atgl protein levels was proven to be mediated by Rald. Altogether, our data suggest that Aldh1 could be a crucial target for treating female visceral obesity. Grant Funding Source : The EHE SEED Grant, The Ohio State University