FRI023 Increased Fibrosis In White Adipose Tissue Of Male And Female bGH Transgenic Mice Appears Independent Of TGF-β Action

Abstract

Abstract Disclosure: G. Lach: None. S. Bell: None. J.A. Young: None. E.O. List: None. R. Basu: None. D. Geitgey: None. K.Y. Lee: None. D. Swegan: None. L.J. Caggiano: None. S. Okada: None. J.J. Kopchick: None. D.E. Berryman: None. Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins, which can disrupt tissue structure and function. Previous work has shown that male bovine growth hormone (bGH) transgenic mice have high levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1), marked decrease in lifespan, and increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these findings, evaluating: 1) WAT fibrosis in female bGH mice, 2) levels of circulating factors implicated in fibrosis, and 3) the role of TGF-β, a central mediator of fibrogenesis, in the development of bGH WAT fibrosis. Our findings confirmed that female bGH mice exhibit increased WAT fibrosis, most prominent in the Sc depot, like male bGH mice, but also significantly increased in the perigonadal depot, unlike male bGH mice. bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover (plasma P1NP, P3NP and ICTP) and FGF21 relative to controls but no genotype-dependent alteration in fibroblast activation protein (FAP). TGF-β and TGF-β signaling in serum or WAT was either unchanged or reduced in male and female bGH mice at both young and mature ages. The treatment of bGH mice with a TGF-β antagonist, pirfenidone, did not attenuate bGH WAT fibrosis. Contrary to the effects of the chronic exposure to excess GH, acute GH treatments in vivo or in vitro did elicit a modest increase in TGF-β signaling. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell population within subcutaneous bGH WAT; however, a striking increase in B lymphocyte infiltration in Sc bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells, particularly B cells, in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and aging. Acknowledgements:This work was sponsored, in part, by ASPIRE grant funding from Pfizer. This work was also supported by the State of Ohio’s Eminent Scholar Program to J. J. K. that includes a gift from Milton and Lawrence Goll and by the startup funds from the Heritage College of Osteopathic Medicine at Ohio University, Athens, OH. Presentation: Friday, June 16, 2023