STAT3 suppresses Wnt/β-catenin signaling during the induction phase of primary Myf5+ brown adipogenesis

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2018-11, Vol.111, p.434-444
• Main Authors: Cantwell, Marc T., Farrar, Jared S., Lownik, Joseph C., Meier, Jeremy A., Hyun, Moonjung, Raje, Vidisha, Waters, Michael R., Celi, Francesco S., Conrad, Daniel H., Harris, Thurl E., Larner, Andrew C.
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipogenesis; Adipogenesis - physiology; Adipose Tissue, Brown - metabolism; Animals; BAT; beta Catenin - metabolism; Cell Differentiation - physiology; Mice; Mice, Inbred C57BL; Myogenic Regulatory Factor 5 - metabolism; Signal Transduction - physiology; STAT3; STAT3 Transcription Factor - metabolism; TYK2 Kinase - metabolism; UCP1; Uncoupling Protein 1 - metabolism; Wnt; Wnt Signaling Pathway - physiology; β-Catenin
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2018.05.023

•STAT3 is required during the induction phase for differentiation of primary brown pre-adipocytes.•Deletion of STAT3 after the induction period does not affect UCP1 protein levels and differentiation.•STAT3 KO cells can be rescued through inhibition of the canonical Wnt/β-Catenin pathway or by knock down of β-catenin.•STAT3 KO cells upregulate Wnt ligands during the induction phase. Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1 (UCP1). We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. The inability of STAT3−/− preadipocytes to differentiate can be rescued using Wnt ligand secretion inhibitors when applied during the induction stage. Through chemical inhibition and RNAi, we show that it is the canonical β-catenin pathway that is responsible for the block in differentiation; inhibition or knockdown of β-catenin can fully rescue adipogenesis and UCP1 expression in the STAT3−/− adipocytes. During the induction stage, Wnts 1, 3a, and 10b have increased expression in the STAT3−/− adipocytes, potentially explaining the increased levels and activity of β-catenin. Our results for the first time point towards an interaction between the JAK/STAT pathway and the Wnt/β-catenin pathway during the early stages of in-vitro adipogenesis.