Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

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Project Summary/Abstract Excess lipids increase the total intramyocellular lipid content and the ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscles, which is one of the main targets of insulin and its action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), activates mineralocorticoid receptors (MRs) to induce muscle lipid metabolic disorders and insulin resistance. Recent data further indicate that cell specific endothelial cell (EC) MR (ECMR) activation mediates WD-induced muscle lipid metabolism disorders, impaired insulin metabolic signaling, and tissue insulin resistance. In this regard, ECMR activation increase CD36 expression in skeletal muscle arterioles and tissues, which promotes excessive free fatty acid trafficking across the muscle vasculature, leading to skeletal muscle lipid accumulation, CD36 palmitoylation and insulin resistance. There is a relationship between microvascular endothelial dysfunction and muscle metabolic disorders and insulin resistance through exosomes. Recent data suggest that EC derived exosomal proteins, such as exosomal CD36, can promote lipid accumulation and metabolic disorders. Upon being released from ECs, exosomal CD36 can be up-taken by the neighboring skeletal muscle and thus promote muscle lipid accumulation. The hypothesis of this application is that activation of ECMRs induces EC CD36 expression and release of EC-derived exosomal CD36 which increases free fatty acid uptake in ECs and translocation to skeletal muscle cells, leading to skeletal muscle intramyocellular lipid deposits and insulin resistance. Objective 1 of this application is to understand the role and mechanisms of ECMR signaling on CD36 expression, free fatty acid uptake in ECs and skeletal muscle cells, and related muscle lipid deposition and insulin resistance. Objective 2 of this application is to investigate the role and mechanisms of enhanced ECMR signaling on the EC-derived exosomal CD36 release and its role in facilitating increased skeletal muscle cell CD36 to further promote muscle fatty acid uptake, IMC lipid deposition and insulin resistance. Accordingly, in vitro cell treated with free fatty acid and in vivo mice fed a WD will be used to set up a model of ECMR/ECCD36 activation, obesity and insulin resistance. The proposed work should provide a better understanding the role of ECMRs and EC exosomal CD36 in the development of skeletal muscle insulin resistance and provide an important biomarker for the early diagnosis and prevention of this increasing cause of diabetes.