A Cardiac Amino-Terminal GRK2 Peptide Inhibits Maladaptive Adipocyte Hypertrophy and Insulin Resistance During Diet-Induced Obesity

Objective: Investigate the effect of cardiac βARKnt expression on metabolic function in response to diet-induced obesity. Background: Heart disease remains the leading cause of death, and mortality rates positively correlate with the presence of obesity and diabetes. The exact mechanisms linking dysfunction in cardiac and systemic metabolism are not fully understood. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiac function using transgenic mice with cardiac restricted expression of a short peptide, βARKnt. Male mice exhibited cardioprotection during chronic pressure overload, enhanced spare respiratory capacity and ATP production using glucose and fatty acids, and reduced abdominal fat weight before and after cardiac stress, potentially due to a novel functional interaction with AKT substrate of 160 kDa (AS160) in the heart. Methods and Results: We subjected animals to high fat diet (HFD) to trigger cardiac and metabolic adaptive changes. Despite equivalent weight gain, unlike the control mice that developed insulin resistance, βARKnt mice exhibited enhanced glucose tolerance and insulin sensitivity, more metabolic flexibility during indirect calorimetry, and increased energy expenditure. As before, βARKnt mice had reduced gonadal white adipose tissue that exhibited improved inflammatory and energetic markers. Surprisingly, neither β3 adrenergic receptor-mediated nor natriuretic peptide adipose tissue activation explained this enhanced thermogenesis. These mice also exhibited enhanced fractional shortening and cardiac output during both acute and chronic HFD stress, and enhanced insulin-mediated AS160 signaling in the heart. Conclusions: These data suggest a cardiac-driven mechanism to ameliorate maladaptive cardiac remodeling and improve systemic metabolic homeostasis during metabolic stress.