CTHRC1 Expression Results in Secretion-Mediated, SOX9-Dependent Suppression of Adipogenesis: Implications for the Regulatory Role of Newly Identified CTHRC1+/PDGFR-Alpha+ Stromal Cells of Adipose

TL;DR

CTHRC1 suppresses fat cell formation by boosting SOX9 activity and is expressed in a specific type of stromal cell in fat tissue.

Contribution

Identifies a novel CTHRC1+/PDGFR-alpha+ stromal cell population and reveals a SOX9-dependent mechanism for CTHRC1's anti-adipogenic effect.

Findings

CTHRC1 expression reduces adipogenesis by suppressing Cebpa and Pparg and increasing SOX9.

SOX9 is essential for CTHRC1's anti-adipogenic activity, as shown by gene knockdown.

CTHRC1 is selectively expressed in PDGFR-alpha+ stromal cells in white adipose tissue.

Abstract

Adipogenesis is regulated by the coordinated activity of adipogenic transcription factors including PPAR-gamma and C/EBP alpha, while dysregulated adipogenesis can predispose adipose tissues to adipocyte hypertrophy and hyperplasia. We have previously reported that Cthrc1-null mice have increased adiposity compared to wildtype mice, supporting the notion that CTHRC1 regulates body composition. Herein, we derived conditioned medium from 3T3-L1 cells expressing human CTHRC1 and investigated its anti-adipogenic activity. This constituent significantly reduced 3T3-L1 cell adipogenic differentiation commensurate to the marked suppression of Cebpa and Pparg gene expression. It also increased the expression of the anti-adipogenic transcription factor SOX9 and promoted its nuclear translocation. Importantly, Sox9 gene knockdown demonstrated that the anti-adipogenic effect produced by this conditioned medium is dependent on SOX9 expression, while its ability to positively regulate SOX9 was attenuated by the application of Rho and Rac1 signaling pathway inhibitors. We also identified the selective expression of CTHRC1 in PDGFRA-expressing cell populations in human white adipose tissue, but not brown or perivascular adipose tissues. Congruently, flow cytometry revealed CTHRC1 expression in PDGFR-alpha+ stromal cells of mouse white adipose tissue, thus defining a novel stromal cell population that could underpin the ability of CTHRC1 to regulate adiposity.

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