Indeed, the present study shows, when prolonged treatment with metformin rescues impaired neurogenesis and cognitive deficits in middle‐aged DIO mice, phosphorylation of AMPK/aPKC ζ/λ/IRS1 serine residues in the hippocampus of those mice occurs regardless of the plasma levels of insulin, FFA, and glucose (Fig. 5A,C,F–H). Here, IRS1 is linked to Cognitive impairment.