A vast body of literature has established GRK2 as a key player in the development and progression of heart failure. GRK2 levels increase in the heart post injury in an attempt to normalize sympathetic overdrive. While initially beneficial, this response becomes maladaptive. Inhibition of GRK2 improves cardiac function post injury in numerous animal models. Recently, discovery of several non-canonical GRK2 targets has expanded our view of this kinase. Amongst these, our lab has identified GRK2 as a negative regulator of cardiac insulin signaling and this is through direct interaction and phosphorylation of the insulin receptor substrate-1 (IRS1). While continuing to study cardiac metabolic aspects of GRK2 manipulation we have uncovered the novel and exciting finding that cardiac GRK2 activity can regulate whole body metabolism. We found that transgenic mice with cardiac-specific overexpression of GRK2 (Tg-GRK2) show resistance to high fat diet (HFD) induced obesity. In contrast, Tg-βARKct mice with cardiac-specific expression of a peptide inhibitor of GRK2, known as the βARKct display an enhanced obesogenic phenotype when fed a HFD. We placed transgenic mice (and their non-transgenic littermate controls) on a high fat diet (60% kcal% fat) or a control diet (10% kcal% fat) for up to 16 weeks. Mice were housed in grouped cages at room temperature (18-22°C). HFD feeding increased white adipose mass in Tg-BARKct mice vs. NLC, whereas adipose mass in Tg-GRK2 mice is lower than NLC animals. Moreover, HFD Tg-βARKct mice exhibit elevated serum leptin levels relative to NLC, indicating development of leptin resistance. The novelty of this finding could bear great clinical significance, not least because these cardiac specific transgenes elicit a global metabolic phenotype implicating the heart as an endocrine organ and GRK2 activity is essential for this new and unexpected finding.