Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD). APP/PS1 mice and their wild-type controls fed either a standard diet or HFD were characterized at the ages of 3, 6 and 10 months by metabolic parameters related to obesity via mass spectroscopy, nuclear magnetic resonance, immunoblotting and immunohistochemistry to quantify how obesity affected AD pathology. The HFD induced substantial peripheral IR leading to central IR. APP/PS1-fed HFD mice had more pronounced IR, glucose intolerance and liver steatosis than their WT controls. The HFD worsened Aβ pathology in the hippocampi of APP/PS1 mice and significantly supported both peripheral and central inflammation. This study reveals a deleterious effect of obesity-related mild peripheral inflammation and prediabetes on the development of Aβ and Tau pathology and neuroinflammation in APP/PS1 mice.

• Keywords
• APP/PS1, Alzheimer’s disease, amyloid-β, glucose intolerance, inflammation, insulin resistance, neuroinflammation, obesity, tau protein,
• MeSH
• Alzheimer Disease * etiology   MeSH
• Amyloid beta-Peptides MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Diet, High-Fat adverse effects   MeSH
• Insulin Resistance * MeSH
• Mice MeSH
• Neuroinflammatory Diseases MeSH
• Inflammation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm11-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm11-PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm11-PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm11-PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm11-PrRP31 and liraglutide in both the periphery and brain.

• Keywords
• Wistar Kyoto rats, astrocytosis, diet-induced obesity, glucose intolerance, lipid metabolism, lipidomics, liraglutide, metabolomics, prolactin-releasing peptide,
• MeSH
• Diet, High-Fat adverse effects   MeSH
• Prolactin-Releasing Hormone pharmacology   MeSH
• Hypoglycemic Agents pharmacology   therapeutic use   MeSH
• Insulin Resistance * MeSH
• Rats MeSH
• Lipids MeSH
• Liraglutide pharmacology   therapeutic use   MeSH
• Mice MeSH
• Obesity drug therapy   MeSH
• Glucose Intolerance * drug therapy   MeSH
• Rats, Inbred WKY MeSH
• Prediabetic State * drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• Hypoglycemic Agents MeSH
• Lipids MeSH
• Liraglutide MeSH