Thymic Stromal Lymphopoietin induces adipose loss through sebum hypersecretion

Abstract Obesity is a serious public health concern. Emerging studies indicate that the immune system can regulate weight and energy homeostasis. Here we show that the cytokine Thymic Stromal Lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Surprisingly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure. Rather, it was caused by the excessive loss of lipids through the skin as sebum, causing mice to develop a striking “greasy hair” phenotype. Inhibition of sebum secretion or depletion of T cells prevented TSLP-driven adipose loss. TSLP-driven white fat loss and sebum hypersecretion were both mediated via the direct activation of CD4+ or CD8+ T cells by TSLP in an antigen-independent manner, and these T cells could be seen infiltrating skin sebaceous glands. Furthermore, we also found that TSLP and T cells regulated sebum release and sebum-associated anti-microbial peptide expression in the skin at steady-state. In human skin, TSLP expression also correlated directly with sebum-associated gene expression. Together, our study establishes a paradigm in which adipose loss can be achieved by sebum hypersecretion and reveals a previously unknown role of adaptive immunity in skin barrier function through the regulation of sebum secretion.