Underlining the primary role of leptin receptors on neuronal cells in body weight homeostasis, selective genetic deletion of LepR in all neurons (using synapsin I-Cre)32 or defined neuronal cell populations, such as those expressing agouti-related peptide33, but not in hepatocytes32, caused severe obesity and diabetes, and the phenotype of db/db mice could be rescued by neuronal re-expression of leptin receptors34,35. This evidence concerns the gene LEPR and obesity due to melanocortin 4 receptor deficiency.