Given that diabetes- and obesity-induced memory impairments were accompanied by the phosphorylation of IRS1 at mSer307 [5], we found that young APPKINL-G-F mice showing normal metabolism and memory function displayed increased phosphorylation of hippocampal IRS1 at three Ser residues including mSer307, mSer612, and mSer1097, in which the Aβ42 level had already increased before the onset of memory decline. Here, IRS1 is linked to obesity due to melanocortin 4 receptor deficiency.