Several factors, including activators of β3-AR (adrenaline, norepinephrine, and β3-AR agonists), inflammatory cytokines tumor necrosis factor α, high-fat diet, and obesity, have been proven to downregulate the expression of ADRB3 through activation of exchange proteins directly activated by cAMP‌ (EPAC)/Ras-related protein Rab-2 A (RAP2A)/phosphoinositide-phospholipase C (PI-PLC) pathway, thus leading to catecholamine resistance in adipocytes [34]. Here, RAP2A is linked to obesity due to melanocortin 4 receptor deficiency.