Acetyl-CoA metabolism determines the partitioning of lipids between adipose tissue and skin [RNA-seq 2]

ATP-citrate lyase (ACLY) generates cytosolic acetyl-CoA for lipid synthesis and is a promising therapeutic target in disease contexts with altered lipid metabolism. Here, we developed inducible whole-body Acly knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis and barrier function. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; and skin-specific double knockout (DKO) of Acly and Acss2 exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of key barrier lipids, the sebaceous glands unexpectedly increase their lipid-rich sebum secretion, supplied in part by fatty acids released from adipose tissues. Accordingly, DKO mice rapidly lose fat mass, and dietary lipid supplementation partially rescues both the lipoatrophy and aberrant skin phenotypes. Thymic stromal lymphopoietin (TSLP), a cytokine with a role in regulating sebaceous glands, is overexpressed in DKO epidermis and thus may stimulate sebum secretion in response to deficient epidermal acetyl-CoA synthesis. Together, the data demonstrate that cytosolic acetyl-CoA synthesis in the skin both maintains local tissue homeostasis and influences systemic lipid partitioning and storage.