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T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/?-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 ? 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/?-catenin pathway; however, TCF7 modulates Gprc6a and Ucp1 promoter activation independent of ?-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.

SUBMITTER: Li Q

PROVIDER: S-EPMC5854832 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Li Qian Q Hua Yue Y Yang Yilin Y He Xinyu X Zhu Wei W Wang Jiyong J Gan Xiaoqing X

Molecular and cellular biology 20180315 7

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 ...[more]

PMID: 29358218

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Project description:The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of β-catenin, which translocates to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of Wnt target genes. When not bound to β-catenin, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a specific lentiviral reporter, we identified hematopoietic tumor cells displaying constitutive TCF/LEF transcriptional activation in the absence of β-catenin stabilization. Suppression of TCF/LEF activity in these cells mediated by an inducible dominant-negative TCF4 (DN-TCF4) inhibited both cell growth and the expression of Wnt target genes. Further, expression of TCF1 and LEF1, but not TCF4, stimulated TCF/LEF reporter activity in certain human cell lines independently of β-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to β-catenin, induced Xenopus embryo axis duplication, a hallmark of Wnt activation, and the expression of the Wnt target gene Xnr3. Through generation of different TCF1-TCF4 fusion proteins, we identified three distinct TCF1 domains that participate in the β-catenin-independent activity of this transcription factor. TCF1 and LEF1 physically interacted and functionally synergized with members of the activating transcription factor 2 (ATF2) family of transcription factors. Moreover, knockdown of ATF2 expression in lymphoma cells phenocopied the inhibitory effects of DN-TCF4 on the expression of target genes associated with the Wnt pathway and on cell growth. Together, our findings indicate that, through interaction with ATF2 factors, TCF1/LEF1 promote the growth of hematopoietic malignancies in the absence of β-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling.

Dataset Information

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

Publications

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

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