A cardiac amino-terminal GRK2 peptide inhibits insulin resistance yet enhances maladaptive cardiovascular and brown adipose tissue remodeling in females during diet-induced obesity

Obesity and metabolic disorders are increasing in epidemic proportions, leading to poor outcomes including heart failure. With a growing recognition of the effect of adipose tissue dysfunction on heart disease, it is less well understood how the heart can influence systemic metabolic homeostasis. Even less well understood is sex differences in cardiometabolic responses. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiometabolic remodeling using transgenic mice with cardiac restricted expression of a short peptide, 8ARKnt. Male mice preserved insulin sensitivity, enhanced metabolic flexibility and adipose tissue health, elicited cardioprotection, and improved cardiac metabolic signaling. To examine the effect of cardiac 8ARKnt expression on cardiac and metabolic function in females in response to diet-induced obesity, we subjected female mice to high fat diet (HFD) to trigger cardiac and metabolic adaptive changes. Despite equivalent weight gain, 8ARKnt mice exhibited improved glucose tolerance and insulin sensitivity. However, 8ARKnt mice displayed a progressive reduction in energy expenditure during cold challenge after acute and chronic HFD stress. They also demonstrated reduced cardiac function and increased markers of maladaptive remodeling and tissue injury, and decreased or aberrant metabolic signaling. 8ARKnt mice exhibited reduced lipid deposition in the brown adipose tissue (BAT), but delayed or decreased markers of BAT activation and function suggested multiple mechanisms contributed to the decreased thermogenic capacity. These data suggest a non-canonical cardiac regulation of BAT lipolysis and function that highlights the need for studies elucidating the mechanisms of sex-specific responses to metabolic dysfunction.