discovery samples that were called for the loss of a PPYR1 gene copy number, only one was homozygous for the deletion. One can only speculate about these seemingly contradictory findings between studies in human and mice. Several mechanisms might explain the difference: (i) mice may not be the most appropriate model to understand the function of the human PPYR1, as mice express a functional Y6 receptor (in humans only an non-functional pseudo gene exists) and this receptor could explain some of the results of the Ppyr1 knockout mice. (ii) Sequence identity between mice Ppyr1 amino acid sequence is only 76% compared with human PPYR1. The high variability of PPYR1 across species might explain its different roles among species. (iii) Ppyr1 knockout mice are hyperphagic but nonetheless lean (27). If the gene has a slightly altered function in humans, hyperphagia is potentially retained but not the lean phenotype. (iv) Compared with the 56 studied subjects who are hemizygous for the PPYR1 gene, Ppyr1 knockout mice have neither copy of the gene nor corresponding gene expression products. Thus, subjects with only one copy of PPYR1 may produce less protein, which will regulate energy homeostasis through agonists or other pathways to inhibit obesity.
