Preadipocyte factor 1 regulates adipose tissue browning via TNF-α-converting enzyme-mediated cleavage.

Increasing adaptive thermogenesis in adipose tissue may be a potential therapeutic target for overcoming obesity and obesity-related disorders. Preadipocyte factor 1 (Pref-1), a preadipocyte secreted protein, plays an inhibitory role in adipogenic differentiation. However, the role of Pref-1 in adipose tissue browning remains unknown. We investigated whether Pref-1 regulates thermogenic program and beige fat biogenesis. Pref-1 expression levels were examined in inguinal white adipose tissue (iWAT) and differentiated 3T3-L1 adipocytes in thermogenic conditions induced by cold exposure or a beta-adrenergic stimulus (CL316,243). Overexpression and knockdown studies were performed both in vivo and in vitro to clarify the role of Pref-1 in iWAT browning. Cold exposure or CL316,243 induced a thermogenic program in adipose tissue of C57BL/6N mice and in 3T3-L1 adipocytes. Notably, Pref-1 levels were down-regulated in iWAT and adipocytes under these conditions. Overexpressing Pref-1 showed reduced thermogenic gene expressions in response to CL316,243 treatment, whereas depletion of Pref-1 augmented thermogenic program in 3T3-L1 adipocytes. Correspondingly, treating C57BL/6N mice with Pref-1 resulted in reduced expression of thermogenic and beige fat markers, a reduced rate of oxygen consumption, blunting of UCP1 expression and beige fat formation in iWAT in response to cold exposure or CL316,243 injection compared to the untreated mice. The opposite phenotype was observed in mice with inducible fat-specific knock-out of Pref-1. Mechanistically, these effects were regulated by modulation of TNF-α-converting enzyme activity and Pref-1 cleavage. Our findings establish a novel role of Pref-1 that regulates adaptive thermogenesis. This offers a unique target for improving energy homeostasis and treating obesity.