The decreased estrogen actions that were observed with age or in males would favor, particularly in the face of a HFD, an insulin-resistant and obesity-related systemic metabolic milieu able to enhance GRK2 upregulation [13,15], whereas the normal estrogen levels in young female mice would counteract the effects of a HFD and thus lessen GRK2 upregulation. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.