Sustained high-fat diet modulates inflammation, insulinsignalling and cognition in mice and a modified xenin peptideameliorates neuropathology in a chronic high-fat model

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Abstract

Aims: To demarcate pathological events in the brain as a result of short-term to chronic highfat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and toassess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.Methods: C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and21 weeks. Cognition was assessed using novel object recognition and the Morris water maze.Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry,quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was alsoadministered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathologicalstage.Results: Recognition memory was consistently impaired in HFD-fed mice and spatial learningwas impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616were increased in the brain on 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 interleukin (IL)-6 and chemokine(C-X-C motif ) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reducedextracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increasedexpression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase β, 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 andinsulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation andinsulin signalling dysregulation and may have therapeutic potential in the treatment of diseasesassociated with neuroinflammation or perturbed insulin signalling in the brain.
LanguageEnglish
Pages1166-1175
Number of pages9
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number5
Early online date11 Feb 2018
DOIs
Publication statusE-pub ahead of print - 11 Feb 2018

Fingerprint

High Fat Diet
Cognition
Fats
Diet
Inflammation
Brain
Toll-Like Receptor 4
Sirolimus
Neuropathology
xenin 25
Chemokine CXCL1
Phosphotransferases
Insulin
Gliosis
Peptide Receptors
Interleukin-5
Inbred C57BL Mouse
Synapses
Protein Kinase C
Interleukin-6

Keywords

  • cognitive function
  • high-fat diet
  • insulin resistance
  • neuroinflammation
  • neurotensin receptor-
  • 1
  • xenin-25

Cite this

@article{0dd4a42a245e42d1b3efb4a42d843732,
title = "Sustained high-fat diet modulates inflammation, insulinsignalling and cognition in mice and a modified xenin peptideameliorates neuropathology in a chronic high-fat model",
abstract = "Aims: To demarcate pathological events in the brain as a result of short-term to chronic highfat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and toassess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.Methods: C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and21 weeks. Cognition was assessed using novel object recognition and the Morris water maze.Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry,quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was alsoadministered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathologicalstage.Results: Recognition memory was consistently impaired in HFD-fed mice and spatial learningwas impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616were increased in the brain on 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 interleukin (IL)-6 and chemokine(C-X-C motif ) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reducedextracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increasedexpression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase β, 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 andinsulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation andinsulin signalling dysregulation and may have therapeutic potential in the treatment of diseasesassociated with neuroinflammation or perturbed insulin signalling in the brain.",
keywords = "cognitive function, high-fat diet, insulin resistance, neuroinflammation, neurotensin receptor-, 1, xenin-25",
author = "Paul Denver and Gault, {Victor A} and McClean, {Paula L}",
year = "2018",
month = "2",
day = "11",
doi = "10.1111/dom.13210",
language = "English",
volume = "20",
pages = "1166--1175",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "5",

}

TY - JOUR

T1 - Sustained high-fat diet modulates inflammation, insulinsignalling and cognition in mice and a modified xenin peptideameliorates neuropathology in a chronic high-fat model

AU - Denver, Paul

AU - Gault, Victor A

AU - McClean, Paula L

PY - 2018/2/11

Y1 - 2018/2/11

N2 - Aims: To demarcate pathological events in the brain as a result of short-term to chronic highfat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and toassess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.Methods: C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and21 weeks. Cognition was assessed using novel object recognition and the Morris water maze.Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry,quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was alsoadministered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathologicalstage.Results: Recognition memory was consistently impaired in HFD-fed mice and spatial learningwas impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616were increased in the brain on 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 interleukin (IL)-6 and chemokine(C-X-C motif ) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reducedextracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increasedexpression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase β, 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 andinsulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation andinsulin signalling dysregulation and may have therapeutic potential in the treatment of diseasesassociated with neuroinflammation or perturbed insulin signalling in the brain.

AB - Aims: To demarcate pathological events in the brain as a result of short-term to chronic highfat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and toassess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.Methods: C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and21 weeks. Cognition was assessed using novel object recognition and the Morris water maze.Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry,quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was alsoadministered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathologicalstage.Results: Recognition memory was consistently impaired in HFD-fed mice and spatial learningwas impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616were increased in the brain on 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 interleukin (IL)-6 and chemokine(C-X-C motif ) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reducedextracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increasedexpression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase β, 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 andinsulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation andinsulin signalling dysregulation and may have therapeutic potential in the treatment of diseasesassociated with neuroinflammation or perturbed insulin signalling in the brain.

KW - cognitive function

KW - high-fat diet

KW - insulin resistance

KW - neuroinflammation

KW - neurotensin receptor-

KW - 1

KW - xenin-25

U2 - 10.1111/dom.13210

DO - 10.1111/dom.13210

M3 - Article

VL - 20

SP - 1166

EP - 1175

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 5

ER -