Anorexigenic Lipopeptides Ameliorate Central Insulin Signaling and Attenuate Tau Phosphorylation in Hippocampi of Mice with Monosodium Glutamate-Induced Obesity

Article type: Research Article

Authors: Špolcová, Andrea^{a; b} | Mikulášková, Barbora^a | Holubová, Martina^a | Nagelová, Veronika^a | Pirnik, Zdenko^{a; e; f} | Zemenová, Jana^{a; d} | Haluzík, Martin^c | Železná, Blanka^a | Galas, Marie-Christine^b | Maletínská, Lenka^{a; *}

Affiliations: [a] Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic | [b] 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 | [c] Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic | [d] Institute of Chemical Technology, Department of Analytical Chemistry, Prague, Czech Republic | [e] Laboratory of Functional Neuromorphology, Institute of Experimental Endocrinology, SAS, Bratislava, Slovak Republic | [f] Department of Human and Clinical Pharmacology, University of Veterinary Medicine, Košice, Slovak Republic

Correspondence: [*] Correspondence to: Dr. Lenka Maletínská, Institute of Organic Chemistry and Biochemistry AS CR, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic. Tel.: +420 220183567; Fax: +420 220183571; E-mail: maletin@uochb.cas.cz.

Abstract: 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.

Keywords: Alzheimer's disease, insulin signaling, liraglutide, monosodium glutamate-obese mice, obesity, pre-diabetes, prolactin-releasing peptide, tau phosphorylation

DOI: 10.3233/JAD-143150

Journal: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 823-835, 2015