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

•Heart disease remains the leading cause of death, in part due to increasing diabetes and obesity, though the exact mechanisms linking these disorders are not fully understood.•In a diet-induced obesity model, we found that cardiac expression of an amino-terminal peptide of GRK2, βARKnt, preserves systemic glucose tolerance and insulin sensitivity despite normal weight gain.•βARKnt enhanced metabolic flexibility, increased energy expenditure, protected against maladaptive visceral adipocyte hypertrophy, and induced visceral fat browning.•βARKnt further elicited cardioprotection and increased insulin-mediated AS160 signaling during metabolic stress.•These data point to a noncanonical cardiac regulation of systemic metabolic homeostasis that may lead to new treatment modalities for metabolic syndrome.