title: Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity.
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.
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Špolcová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Mikulášková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Holubová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Nagelová
authors.affiliation: 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.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Pirnik
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic Institute of Chemical Technology, Department of Analytical Chemistry, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Zemenová
authors.affiliation: Third Department of Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Haluzík
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors.forename: Blanka
authors.initials: B
authors.lastname: Železná
authors.affiliation: 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.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
authors.affiliation: Institute of Organic Chemistry and Biochemistry, AS CR, Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Maletínská
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005421:Flavoring Agents / Q000633:toxicity*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D061385:Insulins / Q000378:metabolism*; D055666:Lipopeptides / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D056690:Prolactin-Releasing Hormone / Q000187:drug effects / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012970:Sodium Glutamate / Q000633:toxicity*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D005421:Flavoring Agents; D061385:Insulins; D055666:Lipopeptides; D056690:Prolactin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D016875:tau Proteins; D052216:Glucagon-Like Peptide 1; D012970:Sodium Glutamate
keywords: Alzheimer's disease; insulin signaling; liraglutide; monosodium glutamate-obese mice; obesity; pre-diabetes; prolactin-releasing peptide; tau phosphorylation