Role of vitamin A metabolism in visceral obesity

Obesity has become a global epidemic in recent years. In the United States, obesity rates are increasing at an alarming rate along with a dramatic rise in morbidity and mortality. A number of studies attribute such mortalities to central/visceral obesity, characterized by increased fat mass in the abdomen. Visceral obesity is closely associated with the prevalence of insulin resistance, type 2 diabetes, cardiovascular diseases, and even some cancers. However, mechanisms underlying visceral obesity are unclear.;This thesis is designed to investigate how vitamin A metabolites retinaldehyde (Rald) and retinoic acid (RA) and their metabolizing enzymes regulate adipogenesis. My work showed that induction of PPARgamma in adipogenesis depends on RA generation by ALDH1 enzymes that give rise to fat formation in depot-and sex-specific manner. Chapter 1 is a literature review of white fat depots, PPARgamma involvement during adipogenesis and vitamin A metabolism. Chapter 2 investigates the molecular mechanisms by which Aldh1a1 or its product RA affects PPARgamma expression in white fat depots. We demonstrated that adipogenesis in vitro is accompanied by RA production, 70 % of which was generated by Aldh1a1. In Aldh1a1-deficient adipocytes, adipogenesis was impaired compared with WT adipocytes due to markedly reduced expression of PPARgamma regulated through ZFP423. These effects were recovered to some extent either by RA stimulation or overexpression of any of the ALDH1 enzymes in Aldh1a1-/- cells. We used Aldh1a1 deficient mice (Aldh1a1-/-tm1Gdu), a mouse model of obesity developed by Duester and colleagues, to demonstrate causal role of Aldh1a1 in obesity in vivo. We found a fat depot-specific expression of Aldh1 enzymes that suggests distinct RA generation in different adipose depots regulating visceral obesity by vitamin A-metabolizing enzymes or by RA.;Chapter 3 investigates sex-and depot-specific fat formation by Rald and RA on a high-fat (HF) diet. Aldh1a1-/-tm1Gdu mice displayed a lean phenotype compared to wild type (WT) on a HF diet associated with markedly higher ATGL protein levels in visceral fat of Aldh1a1 -/-tm1Gdu females vs. males. The sex differences in ATGL protein expression were dependent on disrupted catabolism of Rald in Aldh1-/-tm1Gdu females whereas male mice maintained RA production by Aldha3. The depot and sex-specific RARE activation indicating endogenous RA production was demonstrated in RARELacZ reporter mice. Chapter 4 examines regulation of ATGL protein translation by mammalian target of rapamycin complex 1 (mTORC1).;In summary, our findings uncover a novel role of vitamin A metabolites in transcriptional regulation of PPARgamma through ZFP423 and identifies ATGL as a Rald-sensitive gene that protects from visceral fat accumulation, even on a HF diet. Vitamin A metabolizing enzymes may help to develop new therapeutics preventing and treating visceral obesity.