Date of Award

Fall 12-15-2023

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Igor Prudovsky

Second Committee Member

Volkhard Lindner

Third Committee Member

Calvin Vary

Additional Committee Members

Robert Koza

Ivette Emery

Robert Wheeler

Abstract

Adipogenesis is regulated by the coordinated activity of adipogenic transcription factors, including PPAR-gamma (PPARG) and C/EBP alpha (CEBPA). Thus, dysregulated adipogenesis predisposes adipose tissues to adipocyte hypertrophy and hyperplasia. We have previously reported that mice possessing a homozygous null gene mutation in collagen triple helix repeat-containing protein 1 (CTHRC1) have increased adiposity compared to wildtype mice, supporting the concept that CTHRC1 regulates body composition. Herein, we investigated the anti-adipogenic activity of CTHRC1. Using 3T3-L1 preadipocytes, we showed significantly reduced adipogenic differentiation in the presence of CTHRC1 commensurate to marked suppression of Cebpa and Pparg gene expression. In addition, CTHRC1 increased the expression of the anti-adipogenic factor SOX9 (transcription factor SOX-9) and promoted its nuclear translocation. Importantly, Sox9 gene knockdown demonstrated that the anti-adipogenic effect of CTHRC1 is dependent on SOX9 expression, while the ability of CTHRC1 to regulate SOX9 was attenuated by Rho and Rac1 signaling pathway inhibitors. Collectively, these data support that a CTHRC1-Rho/Rac1-SOX9 signaling axis negatively regulates adipogenesis. We also report selective expression of CTHRC1 in PDGRFA-expressing cell populations in human white adipose tissue, but not brown or perivascular adipose tissues. Congruently, flow cytometry analysis of mouse white adipose tissue revealed CTHRC1 expression in PDGFR-alpha+ stromal cells.

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