Introduction: Adipose tissue fibrosis (ATF) in obesity-driven diabetes is characterized by increased extracellular matrix (ECM) deposition. Cell populations that induce ATF in diabetes have yet to be fully elucidated. Transglutaminase 2 (TGM2) is known to contribute to ECM stabilization. The objective of this study was to investigate adipose tissue macrophage (ATM)-derived TGM2 as a potential modulator of ATF in diabetes.
Methods: C57BL/6 mice were placed on chow diet (CD) or high-fat diet (HFD) for 10 weeks and evaluated for ATF and TGM2 expression in epididymal white adipose tissue (eWAT). Next, TGM2 was silenced in HFD mice via in vivo RNAi silencing to evaluate effects on ATF. Lastly, TGM2 CRISPR-silenced macrophages were co-cultured with differentiating adipocytes and evaluated for adipo/lipogenesis. Readout indices included, picrosirius red, qPCR, western blot, RNAscope, and flow cytometry.
Results: TGM2 and Col6A1 eWAT expression were increased in HFD mice compared to CD. TGM2 was increased within the ATMs from HFD mice, suggesting ATMs as the main TGM2 contributor in eWAT during obesity. Successful silencing of TGM2 within HFD ATMs decreased eWAT fibrosis, plausibly caused by observed changes in abundance of AT pro-inflammatory immune cells in TGM2 silenced mice. Finally, differentiating adipocytes co-cultured with TGM2-silenced macrophages showed reduced adipocyte expansion, supporting the notion that macrophage-derived TGM2 contributes to AT ECM alterations also involved in adipocyte growth.
Conclusion: Results suggest that ATMs secreting TGM2 in HFD mice contribute to ATF in obesity. We identify TGM2 in ATMs as a potential cell-specific candidate marker for therapeutics directed at obesity-associated ATF.
M. Hollis: None. D. Elizondo: None. T. Patel: None. R. Roberson: None. J. Chen: None. J.A. Yanovski: Research Support; Rhythm Pharmaceuticals, Inc., Soleno Pharmaceuticals, Inc, Versanis Bil, Hikma Pharmaceuticals, Inc., National Institutes of Health.
