Effects of Wnt Signaling on Brown Adipocyte Differentiation and Metabolism Mediated by PGC-1α

Abstract

Activation of canonical Wnt signaling inhibits brown adipogenesis of cultured cells by impeding induction of PPARγ and C/EBPα. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1α is required for activation of uncoupling protein 1 (UCP1). Wnt10b blocks brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a β3-agonist. In differentiated brown adipocytes, activation of Wnt signaling suppresses expression of UCP1 through repression of PGC-1α. Consistent with these in vitro observations, UCP1-Wnt10b transgenic mice, which express Wnt10b in interscapular tissue, lack functional brown adipose tissue. While interscapular tissue of UCP1-Wnt10b mice lacks expression of PGC-1α and UCP1, the presence of unilocular lipid droplets and expression of white adipocyte genes suggest conversion of brown adipose tissue to white. Reciprocal expression of Wnt10b with UCP1 and PGC-1α in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of brown adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks brown adipogenesis, whereas activating Wnt signaling in mature brown adipocytes stimulates their conversion to white adipocytes.

ACKNOWLEDGMENTS

This work was supported by grants from the National Institutes of Health to O.A.M. (grants DK51563 and DK62876). Other support was from the University of Michigan Center for Integrative Genomics, Diabetes Research and Training Center, Nathan Shock Mutant and Transgenic Rodent Core, the Jack Lapides Fellowship, and a mentor-based postdoctoral fellowship from the American Diabetes Association.

We thank Mark Ribick and Randy Kaufman for sharing unpublished qPCR primers for C/EBPα, FABP4, and 18S rRNA. Chir99021 was the generous gift of Allan S. Wagman at Chiron Corporation, Emeryville, Calif.