OR22-03 Enhanced Endothelial Mineralocorticoid Receptor Signaling Mediates Diet - Induced Soleus Fat Infiltration And Insulin Resistance

Disclosure: C. Homan: None. J. Habibi: None. D. Chen: None. A. Whaley-Connell: None. J.R. Sowers: None. G. Jia: None. Skeletal muscle is an important organ in the storage and release of lipids in response to physiological changes in free fatty acid (FFA) supply and demand. Once fat tissue mass expansion exceeds its blood supply excess lipids are stored ectopically as small lipid droplets in non-adipose tissues such as skeletal muscle. Recently, our data found that mineralocorticoid receptors (MRs) mediate Western diet (WD)-induced lipid infiltration of skeletal muscle and insulin resistance. Related to this, MRs, the principal receptors for the hormone aldosterone in the kidney, also exist in vascular cells, including endothelial cells (ECs). Moreover, enhanced MR signaling in ECs (ECMR) induces arterial stiffening and impairs microcirculation. However, our understanding of the precise mechanisms by which enhanced ECMR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles of ECMR in soleus lipid accumulation and corresponding insulin resistance in diet-induced obesity. Six-week-old ECMR wild type (ECMR(+/+)) and knockout (ECMR(-/-)) mice were fed either a mouse chow diet or WD for 16 weeks. 16 weeks of WD induced increases in glucose intolerance, fasting plasma insulin levels, HOMA-IR and insulin resistance index were found to be blunted in ECMR(-/-) mice. ECMR(-/-) prevented WD-induced increase in soleus FFA levels without changing serum FFA levels. Meanwhile, WD also increased soleus intramyocellular lipid content, plasma EC derived exosomal CD36 and soleus CD36 protein levels. These abnormalities were related to reduced soleus insulin metabolic signaling in PI3K/Akt pathways, as these pathways were blunted in ECMR(-/-) mice. These findings indicate that EC specific MR activation contributes to diet-induced increases in CD36 expression, soleus fat infiltration, as well as systemic and skeletal muscle insulin resistance. Presentation: Saturday, June 17, 2023