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

ABSTRACT

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 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/β-catenin pathway; however, TCF7 modulates Gprc6a and Ucp1 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.

KEYWORDS:

• TCF7/TCF1
• WNT/β-catenin pathway
• osteocalcin
• GPRC6A
• UCP1
• WNT/β-catenin

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00562-17.

ACKNOWLEDGMENTS

This work was sponsored by the National Natural Science Foundation of China (grant 31671466).

We are grateful to D. Pan and Q. Tang for providing DE-2-3 and C3H10T1/2 cells. We thank Y. Huang and J. Li for confocal microscopy technical help.

Q.L. did constructs, reporter assays, protein interaction assays, cells differentiation, qPCR assays, and cells staining assays; Y.H. and Y.Y. made mouse tissue samples and performed QPCR assays; X.H. and W.Z. did technical work; J.W. supervised the project and wrote the manuscript; X.G. supervised the project and wrote the manuscript.

We declare that we have no conflicts of interest.