Abstract P3097: Sex-related Differences In Immune Responsiveness Of Sarcospan-deficient Mice To Metabolic Stress

This study compares sex-related differences in inflammatory signaling that may contribute to metabolic and cardiovascular disease. The SSPN gene encoding the sarcospan (SSPN) protein has been described as an “obesity-susceptibility” gene. To study the influence of SSPN on metabolic function we subjected young 2-month-old male and female WT and sarcospan-deficient (SSPN -/- ) mice to 4 months high fat diet (HFD) (60% fat). Young male and female SSPN -/- mice exhibited some protection from weight gain and tissue inflammation. Cardiac function was preserved in the SSPN -/- mice of both sexes after HFD. Thus, we became interested in the combined impact of SSPN and metabolic stress on systemic inflammation. To study how metabolic stress impacts activation of anti- and pro-inflammatory pathways the chemokine/cytokine/adipokine proteome was examined in blood serum, heart, white adipose tissue, and liver of male mice. Under control conditions both WT and SSPN -/- male blood serum exhibited low levels of pro-inflammatory molecules, however CXCL 10 and CCL-2 significantly increased in SSPN -/- after HFD. Histological analysis of white adipose tissue (WAT) further revealed that SSPN deficiency may be protective against WAT immune infiltration in both males and females. Proteome analysis of WAT from HFD and control diet males revealed striking alterations in inflammatory signatures, whereas in the heart and liver most significant changes were observed in SSPN -/- controls. Flow cytometry was performed to examine spleen immune cell content of the mice. To elucidate factors contributing to the sex differences observed in the SSPN -/- response to metabolic stress we examined the response of bone marrow derived macrophages (BMDM) obtained from the sex/diet/gender groups included in this study. The BMDM acute response to innate immune ligands was tested at 3 and 6 hours to innate immune ligands and in general, female control diet SSPN -/- BMDMs exhibited enhanced pro-inflammatory responsiveness compared to female HFD and male control diet BMDMs. Overall, these studies describe distinct inflammatory signatures in the heart and WAT and a sex-dependent influence of SSPN -/- on macrophage activation that may have distinct consequences on cardiovascular and metabolic health.