Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity.
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.
['Špolcová|Andrea|A|', 'Mikulášková|Barbora|B|', 'Holubová|Martina|M|', 'Nagelová|Veronika|V|', 'Pirnik|Zdenko|Z|', 'Zemenová|Jana|J|', 'Haluzík|Martin|M|', 'Železná|Blanka|B|', 'Galas|Marie-Christine|MC|', 'Maletínská|Lenka|L|']
D000704:Analysis of Variance D000818:Animals D001835:Body Weight D004195:Disease Models, Animal D005421:Flavoring Agents D052216:Glucagon-Like Peptide 1 D005951:Glucose Tolerance Test D006624:Hippocampus D061385:Insulins D055666:Lipopeptides D008297:Male D051379:Mice D009765:Obesity D010766:Phosphorylation D056690:Prolactin-Releasing Hormone D043562:Receptors, G-Protein-Coupled D015398:Signal Transduction D012970:Sodium Glutamate D013997:Time Factors D016875:tau Proteins
insulin signaling tau phosphorylation obesity Alzheimer's disease pre-diabetes prolactin-releasing peptide liraglutide monosodium glutamate-obese mice