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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 β 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 theGprc6a 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 ofGprc6a in osteocalcin-mediated activation of thermogenic genes. For the first time, we identifiedTcf7 andWnt3a 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/β-catenin pathway; however, TCF7 modulatesGprc6a andUcp1 promoter activation independent of β-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.

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