UC Irvine

Calorie restriction is associated with increasing longevity, delaying skin aging, and mitigating skin tumorigenesis. The effects of feeding and fasting on skin are understudied, and the molecular signals that mediate the skin effects of fasting are not understood. We found that fasting upregulates expression of the rate limiting enzyme of ketogenesis, mitochondrial 3-hydroxy-methylglutaryl-CoA synthase (Hmgcs2), in the interfollicular epidermis and outer root sheath of hair follicles. Ex vivo skin produces β-hydroxybutyrate (BHB), suggesting that fasting leads to local ketogenesis in skin. Fasting also decreases proliferation of IFE stem cells, an effect mediated through the inhibition of canonical Wnt signaling, which was rescued after epidermal deletion of Hmgcs2. After barrier disruption, IFE stem cells in fasting mice proliferate at a lower rate than in fed mice, prioritizing differentiation to re-establish the barrier. Upon feeding, insulin signaling rapidly represses epidermal Hmgcs2 expression by reducing FOXO1 and increasing PPARγ binding at the Hmgcs2 enhancer and promoter. Our findings suggest that HMGCS2 acts as a nutritional sensor, producing epidermal ketone bodies in fasting that shift IFE stem cells from activation to quiescence.