Overall, our data suggest that, in young females, estrogens and the limited upregulation of GRK2 upon a HFD would cooperate to keep most metabolic alterations at bay, whereas in situations of diet-induced obesity in more aged individuals, decreased estrogen actions and upregulated GRK2 levels would reinforce each other, triggering a vicious loop that would help to establish an overt obesity, pro-inflammatory, and insulin-resistant phenotype. Here, GRK2 is linked to obesity disorder.