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Activation of κ-opioid receptor (KOR) ameliorates myocardial ischemia/reperfusion (I/R) injury; however, cardioprotective effects of KOR stimulation disappear in type 1 diabetic subjects with hyperglycemia. The molecular mechanisms underlying this phenomenon remain unknown. Here we found that KOR expression was obviously downregulated and KOR agonism-induced contractile-regulatory and cardioprotective effects were significantly impaired in hearts isolated from streptozotocin (STZ) injection-induced diabetic mice. These in vivo data identified cardiac KOR desensitization as a novel characteristic of the diabetic heart. In cultured cardiomyocytes, high glucose (HG) caused obvious KOR downregulation, accompanied by an upregulation of G protein coupled receptor kinase-2 (GRK2). We found that HG exposure increased the interaction between GRK2 and KOR. More importantly, HG-induced KOR downregulation was reversed by small interfering RNA (siRNA)-mediated GRK2 inhibition. GRK2 knockdown also restored KOR agonism-mediated protection against simulated I/R injury in cardiomyocytes. These in vitro data revealed an essential role of GRK2 in HG-induced KOR desensitization. Finally, cardiac-specific GRK2 knockdown by intramyocardial siRNA injection blocked KOR downregulation and restored contractile-regulatory and cardioprotective effects of KOR agonism in hearts of diabetic mice. In conclusion, these data for the first time demonstrate that GRK2 upregulation is largely responsible for cardiac KOR desensitization in diabetic individuals, which provides novel insights into the management of myocardial I/R injury in patients with diabetes. [ABSTRACT FROM AUTHOR]

Obesity has become a worldwide pandemic and is associated with various metabolic diseases such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. Fas-activated serine/threonine kinase (Fastk) is a multifunctional protein localized in the mitochondrion; however, the role of Fastk in obesity-related metabolic disorders remains unexplored. Here we found that Fastk expression was specifically induced in livers of high fat (HF) diet-fed mice and in saturated fatty acid (such as palmitate)-loaded hepatocytes. Genetic ablation of Fastk ameliorated HF diet-induced insulin resistance, glucose intolerance, and hepatic steatosis. Further studies confirmed that Fastk knockout suppressed hepatic gluconeogenesis and lipogenesis in HF diet-stressed livers and in palmitate-loaded hepatocytes. Mechanistically, Fastk ablation significantly preserved sirtuin-1 (SIRT1) expression and activity in livers of HF diet-fed mice and in palmitate-loaded hepatocytes. Inhibition of SIRT1 activity by EX-527 (a specific inhibitor of SIRT1) totally abolished the suppressive effects of Fastk knockout on gluconeogenesis and lipogenesis in cultured hepatocytes. In conclusion, these data for the first time demonstrate that Fastk critically controls hepatic gluconeogenesis and lipogenesis mainly through modulating SIRT1 signaling. Intervening Fastk expression or activity might be a promising therapeutic strategy for the treatment of obesity-associated metabolic diseases. Image 1 • Fastk is specifically induced in livers of obese individuals and in saturated fatty acid-loaded hepatocytes. • Fastk is a key modulator of hepatic gluconeogenesis and lipogenesis. • Genetic knockout of Fastk ameliorates obesity-associated metabolic disorders. • Fastk is a novel therapeutic target for prevention of obesity-associated metabolic diseases. [ABSTRACT FROM AUTHOR]