1769-P: Development of Adipose Fibrosis and Dysfunction in Aged Rxfp1-/- Mice

Abstract

The hormone relaxin has roles in insulin sensitivity and age-related fibrosis in several organs, but the effect on adipose is unknown. Given the association of adipose fibrosis to dysfunction and progression of metabolic disease, we analyzed adipose tissue in aged mice lacking the relaxin receptor RXFP1. Male and female Rxfp1-/- or age-matched wild type (WT) mice were used at full adulthood (5-7 months) or when aged (12-18 months). Total fat and lean mass was determined, then gonadal white adipose tissue (gWAT) or inguinal white adipose tissue (iWAT) was collected. Sections were stained with Sirius red to visualize collagen. Gene expression was determined by qPCR, and serum adiponectin measured by ELISA. There were no significant differences in total body fat or lean mass between WT and Rxfp1-null mice at either age. All mice had similar adipose collagen content at age 5-7 months. In aged male mice, there was a remarkable increase in collagen in the iWAT of Rxfp1-/- mice, including pericellular deposits and thick collagen fibrils, and modestly elevated gWAT collagen compared to WT. In aged female mice, Rxfp1-null mice had modestly increased pericellular collagen in iWAT, but no apparent difference in gWAT. In aged male iWAT, the expression of the collagen types I, III, and VI genes, and the lysyl oxidase genes Lox, Loxl1, and Loxl2 were all significantly elevated. Serum adiponectin was significantly reduced in Rxfp1-/- mice compared to WT (12.6±1.6 vs. 23.9±2.8 ug/ml respectively, p<.02). In summary, Rxfp1-/- mice developed age-related adipose fibrosis, particularly in the iWAT. The effect was sex-specific, in that the fibrosis was much more extensive in male mice. The Rxfp1-/- mice had increased expression of fibrotic collagen and lysyl oxidase genes, and decreased serum adiponectin, suggesting adipose dysfunction. These results suggest that disruption of relaxin signaling plays a role in preventing age-related adipose fibrosis, which could contribute to the development and progression of metabolic dysfunction. Disclosure R. Bennett: None. F. Hamel: None. R.L. Simpson: None. A.I. Agoulnik: None. Funding U.S. Department of Veterans Affairs