Sustained high fat diet modulates inflammation, insulin signalling and cognition in mice and a modified xenin peptide ameliorates neuropathology in a chronic high fat model.

Sustained high fat diet modulates inflammation, insulin signalling and cognition in mice and a modified xenin peptide ameliorates neuropathology in a chronic high fat model.

Diabetes Obes Metab. 2018 Jan 05;:

Authors: Denver P, Gault VA, McClean PL

Abstract
AIMS: Metabolic disease increases risk of Alzheimer's disease and cognitive dysfunction. Chronic high fat diet (HFD) feeding leads to cognitive impairment and neuroinflammation. This study demarcated pathological events in brain as a result of short-term to chronic HFD feeding. Efficacy of Xenin-25[Lys(13)PAL] was assessed in chronic HFD-fed mice.
METHODS: C57BL/6 mice were fed HFD or normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and Morris water maze. Markers of insulin signaling and inflammation were measured in brain and plasma using immunohistochemistry, qPCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage.
RESULTS: Recognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616 were increased in the brain at day 18 in HFD-fed mice and were reduced by Xenin-25[Lys(13)PAL] in 21-week HFD-fed mice. In plasma, HFD feeding elevated IL-6 and CXCL1 at day 34 and IL-5 at week 10. In brain, HFD feeding reduced ERK2, mTOR, NF-κB1, PKCθ and TLR4 mRNA at week 10 and increased expression of GLP-1R, IKKβ, ERK2, mTOR, NF-κB1, PKCθ and TLR4 at week 21, elevations that were abrogated by Xenin-25[Lys(13)PAL].
CONCLUSIONS: HFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.

PMID: 29316242 [PubMed - as supplied by publisher]

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