Adipocyte lipolysis abrogates skin fibrosis in a Wnt/DPP4-dependent manner

Tissue fibrosis in many organs results from altered and excessive extracellular matrix (ECM) protein deposition [1][1]. Concomitant with ECM expansion, resident lipid-filled cells including mature adipocytes are lost in human and mouse fibrosis[2][2]-[5][3], yet the mechanisms that drive mature adipocyte lipid loss and their contribution to tissue fibrosis are unknown. Here, we identify an early, fibro-protective role of mature adipocyte lipolysis driven by Wnt signaling during fibrosis onset. Using chemical and genetic mouse models of skin fibrosis, we show that fibrotic stimuli induce and maintain lipolysis in mature dermal adipocytes. Loss of the lipolytic rate-limiting enzyme adipocyte triglyceride lipase (ATGL ) [6][4],[7][5] in murine dermal adipocytes exacerbates bleomycin-induced fibrosis development. Adipocyte lipolysis is stimulated in the early stages of Wnt signaling-induced skin fibrosis and by Wnt agonists in vitro . Furthermore, deletion or inhibition of the Wnt target gene, CD26/Dipeptidyl peptidase 4 (DPP4) prevented Wnt-induced lipolysis and skin fibrosis in mice. Notably, DPP4 expression correlates with skin fibrosis severity in human patients. Thus, we propose that adipocyte-derived fatty acids and the Wnt-DPP4 axis act as essential regulators of ECM homeostasis within tissues and provide a therapeutic avenue to manipulate fibrosis. ### Competing Interest Statement Competing interests: R.L. has received consulting fees from Bristol Myers Squibb, Boehringer Ingelheim, Certa, Pfizer, Magenta, Biogen and Formation, and grant support from Biogen, Formation, Moderna, Astra Zeneca, Kyowa, Kirin, and Genentech/Roche. The other authors state no conflict of interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-5 [4]: #ref-6 [5]: #ref-7