![]() Importantly, CD36 also is present in exosomes, which shuttle CD36 between neighboring cells, and have been implicated as mediators in diet-induced lipid metabolic disorders and metabolic syndrome ( 9, 10). Recent studies have indicated that CD36 in endothelial cells (ECs) is very important due to EC CD36 acting as a gatekeeper for parenchymal cell (skeletal muscle cell) FFA uptake and thus directly affects downstream actions on glucose utilization and insulin action in skeletal muscle ( 7, 8). Related to this, CD36 is a fatty acid translocase that enhances cellular FFA uptake and corresponding development and progression of lipid disorders, atherosclerosis, and metabolic syndrome ( 5, 6). Our recent data indicates CD36 mediates the activated MR-induced excessive free fatty acid (FFA) uptake and ectopic lipid accumulation associated with systemic and tissue-specific insulin resistance ( 2, 4). Conversely, inhibition of MRs with spironolactone prevents WD-induced systemic, liver, and skeletal muscle insulin resistance ( 2, 4). Our recent studies have shown that consumption of a diet high in fat and refined sugars, a Western diet (WD), increases plasma aldosterone levels ( 3) and activates MRs ( 2, 4) to directly impair insulin metabolic signaling in protein kinase B (Akt) phosphorylation/activation. Inappropriate tissue-specific MR activation engages in the pathophysiology of insulin resistance ( 1, 2). Recent data indicate that MRs also exist in tissues outside the kidney, including pancreatic islets, adipose, skeletal muscle, liver, and cardiovascular tissue ( 1). Mineralocorticoid receptors (MRs), the primary receptors for the hormone aldosterone, play a key role in plasma volume, electrolyte homeostasis, and blood pressure ( 1). ![]() These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC-derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance. Moreover, in vitro and in vivo activation of ECMR increased EC-derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. Additionally, ECMR −/− also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. ECMR −/− mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16 weeks. Six-week-old female ECMR knockout (ECMR −/−) and wild-type (ECMR +/+) mice were fed either a WD or a chow diet for 16 weeks. Here, we have further investigated whether endothelial cell (EC)–specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance, and dysfunction. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induce CD36 expression, increase ectopic lipid accumulation, and result in systemic and tissue insulin resistance. Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin–angiotensin–aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance.
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