Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3β (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation.

3rd Department of Medicine 1st Faculty of Medicine Charles University Prague Prague Czech Republic

INSERM UMR837 Lille France Jean Pierre Aubert Research Centre Faculté de Médecine Pòle Recherche Institut de Médecine Prédictive et de Recherche Thérapeutique Université Droit et Santé de Lille CHU Lille Lille France

Institute of Organic Chemistry and Biochemistry AS CR Prague Czech Republic

Institute of Organic Chemistry and Biochemistry AS CR Prague Czech Republic INSERM UMR837 Lille France Jean Pierre Aubert Research Centre Faculté de Médecine Pòle Recherche Institut de Médecine Prédictive et de Recherche Thérapeutique Université Droit et Santé de Lille CHU Lille Lille France

Institute of Organic Chemistry and Biochemistry AS CR Prague Czech Republic Institute of Chemical Technology Department of Analytical Chemistry Prague Czech Republic

Institute of Organic Chemistry and Biochemistry AS CR Prague Czech Republic Laboratory of Functional Neuromorphology Institute of Experimental Endocrinology SAS Bratislava Slovak Republic Department of Human and Clinical Pharmacology University of Veterinary Medicine Košice Slovak Republic

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