Follistatin Targets Distinct Pathways To Promote Brown Adipocyte Characteristics in Brown and White Adipose Tissues

• Published in: Endocrinology (Philadelphia) Vol. 158; no. 5; pp. 1217 - 1230
• Main Authors: Singh, Rajan, Braga, Melissa, Reddy, Srinivasa T., Lee, Se-Jin, Parveen, Meher, Grijalva, Victor, Vergnes, Laurent, Pervin, Shehla
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.05.2017; Oxford University Press
• Subjects: 3T3-L1 Cells; Adipocytes; Adipocytes, Brown - physiology; Adipocytes, White - physiology; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - anatomy & histology; Adipose Tissue, Brown - physiology; Adipose Tissue, White - anatomy & histology; Adipose Tissue, White - physiology; Animal tissues; Animals; Browning; Cell Differentiation - genetics; Cell Transdifferentiation - genetics; Cells, Cultured; Differentiation; Editor's Choice; Embryo fibroblasts; Embryo, Mammalian; Embryos; Endocrinology; Female; Fibroblasts; Follistatin; Follistatin - blood; Follistatin - genetics; Follistatin - physiology; Follistatin gene; Gene expression; Inhibition; Male; MAP kinase; Markers; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscles; Myf5 protein; Pharmacology; Protein expression; Proteins; Ribonucleic acid; RNA; Rodents; Signal Transduction - genetics; Skeletal muscle; Special Section: Metabolism in Endocrine Health and Disease; Thermogenesis - genetics; Transgenic mice; Uncoupling protein 1
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1607

Abstract We previously demonstrated that Fst expression is highest in brown adipose tissue (BAT) and skeletal muscle, but is also present at substantial levels in epididymal and subcutaneous white adipose tissues (WATs). Fst promotes mouse brown preadipocyte differentiation and promotes browning during differentiation of mouse embryonic fibroblasts. Fst-transgenic (Fst-Tg) mice show substantial increases in circulating Fst levels and increased brown adipose mass. BAT of Fst-Tg mice had increased expression of brown adipose-associated markers including uncoupling protein 1 (UCP1), PRDM16, PGC-1α, and Glut4. WATs from Fst-Tg mice show upregulation of brown/beige adipose markers and significantly increased levels of phosphorylated p38 MAPK/ERK1/2 proteins compared with the wild-type (WT) mice. Pharmacological inhibition of pp38 MAPK/pERK1/2 pathway of recombinant mouse Fst (rFst) treated differentiating 3T3-L1 cells led to significant blockade of Fst-induced UCP1 protein expression. On the other hand, BAT from Fst-Tg mice or differentiating mouse BAT cells treated with rFst show dramatic increase in Myf5 protein levels as well as upregulation of Zic1 and Lhx8 gene expression. Myf5 levels were significantly downregulated in Fst knock-out embryos and small inhibitory RNA–mediated inhibition of Myf5 led to significant inhibition of UCP1, Lhx8, and Zic1 gene expression and significant blockade of Fst-induced induction of UCP1 protein expression in mouse BAT cells. Both interscapular BAT and WAT tissues from Fst-Tg mice display enhanced response to CL316,243 treatment and decreased expression of pSmad3 compared with the WT mice. Therefore, our results indicate that Fst promotes brown adipocyte characteristics in both WAT and BAT depots in vivo through distinct mechanisms. Follistatin promotes brown adipocyte characteristics by targeting distinct pathways in white and brown adipose tissues.