Vitamin A in brown and white adipose development

Bo Wang

Obesity has become one of the greatest challenges to human health. A positive energy balance, either from too high energy intake, too low energy expenditure or both will eventual increase lipids accumulation in adipocytes. Hypertrophy of adipocytes results in metabolic dysfunction. Brown adipocytes and beige adipocytes increase energy expenditure through thermogenic activity. Activating brown or beige adipocytes prevent diet induced obesity and increase insulin sensitivity. In this dissertation, the effects of vitamin A and RA on white and brown/beige adipogenesis were examined by a series of studies. (1) Firstly, RA blocked white adipogenesis via inhibiting expression of Zfp423, a key transcription factor maintaining white adipose identity. RA induces RAR and ING1 interaction and inhibits Gadd45a expression, which prevents GADD45A mediated Zfp423 DNA demethylation. (2) On the other hand, RA induces brown/beige adipogenesis via enhancing adipose vasculature and beige adipocyte differentiation. RA increases Vegfa transcription through retinoic acid receptor that binds to the Vegfa promoter. VEGFA/VEGFR2 signaling promotes proliferation of PDGFRα+ adipose progenitor cells, and synergizes with RA signaling to upregulate Prdm16 expression and beige adipogenesis in a p38MAPK dependent manner. (3) Moreover, RA signaling is required for cold and β-adrenergic signaling induced brown/beige adipogenesis. Cold exposure or β-adrenergic signaling upregulates aldehyde dehydrogenase 1 family member A1 (Aldh1a1) which elevates RA levels in blood and white adipose tissue, and blockage of RA signaling either by chemical or gene mutation inhibits cold or β-adrenergic signaling induced white adipose tissue browning. (4) Vitamin A or retinoic acid (RA) administration to pregnant mice expanded PDGFRα+ adipose progenitor population in progeny, accompanied by increased blood vessel density and enhanced brown-like (beige) phenotype in white adipose tissue, protecting offspring from diet induced obesity. (5) Moderate alcohol intake induces thermogenic brown/beige adipocyte formation and promotes glucose and lipid oxidation via the elevation of retinoic acid signaling. Taking together, RA acts as a key regulator of adipose tissue development via controlling the expression of early adipogenic genes.

Vitamin A in brown and white adipose development

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