Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.

Background Type-2 diabetes and obesity independently increases the risk of heart failure via incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in hearts of subjects with type-2 diabetes and obesity. Methods High fat diet feeding was used to induce obesity and diabetes in wild type mice or mice lacking β2-adrenergic receptor (β2AR) or β-arrestin2. Wild type mice fed with high fat diet were treated with β-blocker carvedilol or G-protein receptor kinase 2 (GRK2) inhibitor. We examined the signaling and cardiac contractile function. Results High fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced PKA phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with diabetes. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and (GRK2) and β-arrestin2-dependent transactivation of a β2AR-ERK signaling cascade. Thus pharmacological inhibition of β2AR or GRK2, or genetic deletion of β2AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of ERK and PDE4D induction, to prevent diabetes-related contractile dysfunction. Conclusions These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type-2 diabetes.

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.