The major novel findings of the present study are as follows: (i) chronic administration of GLP-1 (7–36) and/or a GLP-1R agonist inhibits the obesity-induced increase in β-cell mass and proliferation; (ii) these treatments activate both the hepatic afferent nerves and pancreatic efferent nerves through the central nervous system (CNS); (iii) this neural relay system is involved in the activation of neurons in the hypothalamus and adrenergic signalling to the pancreas. Here, GLP1R is linked to obesity due to melanocortin 4 receptor deficiency.