Cell-autonomous activation of Hedgehog signaling inhibits brown adipose tissue development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 16; pp. 5069 - 5074
• Main Authors: Nosavanh, LaGina, Yu, Da-Hai, Jaehnig, Eric J., Tong, Qiang, Shen, Lanlan, Chen, Miao-Hsueh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21-04-2015; National Acad Sciences
• Subjects: Adipocytes, Brown - cytology; Adipocytes, Brown - metabolism; Adipose Tissue, Brown - cytology; Adipose Tissue, Brown - embryology; Adipose Tissue, Brown - metabolism; Animals; Biological Sciences; Cell Differentiation - genetics; Cells; Cilia - metabolism; COUP Transcription Factor II - metabolism; Hedgehog Proteins - metabolism; Mice; Musculoskeletal system; Signal Transduction - genetics; Tissues; Up-Regulation - genetics; brown adipose tissue; Hedgehog signaling; cell fate
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1420978112

Significance The function of brown adipose tissue (BAT), which converts chemical energy into heat, has been widely characterized, but how BAT forms and what signaling molecules regulate its formation are largely unknown. In this paper, we report that Hedgehog (Hh) signaling inhibits the formation of BAT during development. Activation of Hh signaling, specifically in the BAT of mice during development, resulted in the loss of interscapular BAT due to the impairment of brown-preadipocyte differentiation. Remarkably, the majority of the BAT cells in the neck were replaced by skeletal muscle-like cells in embryos with elevated Hh activity. These findings indicate that Hh is an essential regulator of BAT development and that developing BAT depots respond differentially to Hh signaling.
Although recent studies have shown that brown adipose tissue (BAT) arises from progenitor cells that also give rise to skeletal muscle, the developmental signals that control the formation of BAT remain largely unknown. Here, we show that brown preadipocytes possess primary cilia and can respond to Hedgehog (Hh) signaling. Furthermore, cell-autonomous activation of Hh signaling blocks early brown-preadipocyte differentiation, inhibits BAT formation in vivo, and results in replacement of neck BAT with poorly differentiated skeletal muscle. Finally, we show that Hh signaling inhibits BAT formation partially through up-regulation of chicken ovalbumin upstream promoter transcription factor II ( COUP-TFII ). Taken together, our studies uncover a previously unidentified role for Hh as an inhibitor of BAT development.