T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/β-Catenin Pathway

Osteocalcin has recently been shown to regulate energy homeostasis through multiple pathways. Adipose tissue is a main organ of energy metabolism, and administration of recombinant osteocalcin in mice promoted energy consumption, thus counteracting obesity and glucose intolerance. The regulation of osteocalcin in islet beta cells has been well documented; however, it is unknown whether osteocalcin can also act on adipocytes and, if it does, how it functions. Here, we provide evidence to demonstrate a specific role for osteocalcin in brown adipocyte thermogenesis. Importantly, expression of the Gprc6a gene encoding a G protein-coupled receptor as an osteocalcin receptor was activated by brown fat-like differentiation. Moreover, Gprc6a expression could be further potentiated by osteocalcin. Meanwhile, overexpression and knockdown experiments validated the crucial role of Gprc6a in osteocalcin-mediated activation of thermogenic genes. For the first time, we identified Tcf7 and Wnt3a as putative targets for osteocalcin signaling. T cell factor 7 (TCF7) belongs to the TCF/LEF1 family of DNA binding factors crucial for the canonical WNT/beta-catenin pathway; however, TCF7 modulates Gprc6a and Ucp1 promoter activation independent of beta-catenin. Further studies revealed that the thermogenesis coactivator PRDM16 and the histone demethylase LSD1 might be required for TCF7 activity. Hence, our study described a TCF7-dependent feedback control of the osteocalcin-GPRC6A axis in brown adipocyte physiologies.