biostudies-literature00480Tanokashira DNIA NIH HHSNIDDK NIH HHSNational Center for Geriatrics and GerontologyMinistry of Education, Culture, Sports, Science and TechnologyJapan Society for the Promotion of Science148-154https://www.ebi.ac.uk/biostudies/studies/S-EPMC8361845biostudies-literatureUnknown559Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance, has been recognized as a risk factor for cognitive impairment and dementia, including Alzheimer's disease (AD). Insulin receptor substrate2 (IRS2) is a major component of the insulin/insulin-like growth factor-1 signaling pathway. Irs2 deletion leads to life-threatening T2DM, promoting premature death in male mice regardless of their genetic background. Here, we showed for the first time that young adult male mice lacking Irs2 on a C57BL/6J genetic background (Irs2^-/-/6J) survived in different experimental environments and displayed hippocampus-associated behavioral alterations. Young adult male Irs2^-/-/6J mice also exhibit aberrant alterations in energy and nutrient sensors, such as AMP-activated protein kinase (AMPK) and glucose transporter3 (GLUT3), and reduced core body temperature accompanied by abnormal change in the temperature sensor in the brain. These results suggest that Irs2 deficiency-induced impairments of brain energy metabolism and thermoregulation contribute to hippocampus-associated behavioral changes in young adult male mice.Biochemical and biophysical research communicationsIrs2 deficiency alters hippocampus-associated behaviors during young adulthood.PMC8361845JP17H02188R01 DK098655K12 DK094721R01 AG067913JP15K12703Maruyama MTaguchi AWang WKuroiwa CTanokashira DWhite MF48falseIrs2 deficiency alters hippocampus-associated behaviors during young adulthood.Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance, has been recognized as a risk factor for cognitive impairment and dementia, including Alzheimer's disease (AD). Insulin receptor substrate2 (IRS2) is a major component of the insulin/insulin-like growth factor-1 signaling pathway. Irs2 deletion leads to life-threatening T2DM, promoting premature death in male mice regardless of their genetic background. Here, we showed for the first time that young adult male mice lacking Irs2 on a C57BL/6J genetic background (Irs2^-/-/6J) survived in different experimental environments and displayed hippocampus-associated behavioral alterations. Young adult male Irs2^-/-/6J mice also exhibit aberrant alterations in energy and nutrient sensors, such as AMP-activated protein kinase (AMPK) and glucose transporter3 (GLUT3), and reduced core body temperature accompanied by abnormal change in the temperature sensor in the brain. These results suggest that Irs2 deficiency-induced impairments of brain energy metabolism and thermoregulation contribute to hippocampus-associated behavioral changes in young adult male mice.2021-01-01T00:00:00Z2021 Jun2024-12-03T23:13:58.511Z2022-02-11T06:49:08.843ZS-EPMC83618453394038610.1016/j.bbrc.2021.04.101