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Ageing potentiates diet-induced glucose intolerance, ?-cell failure and tissue inflammation through TLR4.

ABSTRACT: Ageing and obesity are two major risk factors for the development of type 2 diabetes (T2D). A chronic, low-grade, sterile inflammation contributes to insulin resistance and ?-cell failure. Toll-like receptor-4 (TLR4) is a major pro-inflammatory pathway; its ligands as well as downstream signals are increased systemically in patients with T2D and at-risk individuals. In the present study we investigated the combined effects of high fat/high sucrose diet (HFD) feeding, ageing and TLR4-deficiency on tissue inflammation, insulin resistance and ?-cell failure. In young mice, a short-term HFD resulted in a mildly impaired glucose tolerance and reduced insulin secretion, together with a ?-cell mass compensation. In older mice, HFD further deteriorated insulin secretion and induced a significantly impaired glucose tolerance and augmented tissue inflammation in adipose, liver and pancreatic islets, all of which was attenuated by TLR4 deficiency. Our results show that ageing exacerbates HFD-induced impairment of glucose homeostasis and pancreatic ?-cell function and survival, and deteriorates HFD-induced induction of mRNA expression of inflammatory cytokines and pro-inflammatory macrophage markers. TLR4-deficiency protects against these combined deleterious effects of a high fat diet and ageing through a reduced expression of inflammatory products in both insulin sensitive tissues and pancreatic islets.

SUBMITTER: He W

PROVIDER: S-EPMC5807311 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Ageing potentiates diet-induced glucose intolerance, β-cell failure and tissue inflammation through TLR4.

He Wei W Yuan Ting T Choezom Dolma D Hunkler Hannah H Annamalai Karthika K Lupse Blaz B Maedler Kathrin K

Scientific reports 20180209 1

Ageing and obesity are two major risk factors for the development of type 2 diabetes (T2D). A chronic, low-grade, sterile inflammation contributes to insulin resistance and β-cell failure. Toll-like receptor-4 (TLR4) is a major pro-inflammatory pathway; its ligands as well as downstream signals are increased systemically in patients with T2D and at-risk individuals. In the present study we investigated the combined effects of high fat/high sucrose diet (HFD) feeding, ageing and TLR4-deficiency o ...[more]

PMID: 29426925

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Project description:BackgroundAloe emodin (AE) is a lipid-lowering agent, which could be used to treat hyperlipidemia, thereby reducing the risk of cardiovascular disease. Recent evidence suggests that hyperlipidemia is associated with many cardiac pathological alterations and might worsen myocardial damages.PurposeThe purpose of this study is to evaluate the potential roles and mechanisms of AE in hyperlipidemia-induced oxidative stress and inflammation in the heart. Study Design. We established a hyperlipidemia-induced cardiac inflammation model in rats and cells then administered AE and observed its effect on hyperlipidemia-induced cardiac inflammation.MethodsWe used a mouse model of hyperlipidemia caused by a high-fat diet (HFD) for 10 weeks and cell culture experimental models of inflammation in the heart stimulated by PA for 14 h. Inflammatory markers were detected by qRT-PCR, WB, and immunofluorescence.ResultsWe demonstrated that the expression levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our in vitro study showed AE treatment dose-dependently decreased the expression of IL-1β, IL-6, and TNF-α were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our κB, and p-P65l in vivo and in vitro study showed AE treatment dose-dependently decreased the expression of IL-1.ConclusionTaken together, our findings disclose that AE could alleviate HFD/PA-induced cardiac inflammation via inhibition of the TLR4/NF-κB signaling pathway. Thus, AE may be a promising therapeutic strategy for preventing hyperlipidemia-induced myocardial injury.κB, and p-P65l.

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Ageing potentiates diet-induced glucose intolerance, ?-cell failure and tissue inflammation through TLR4.

Publications

Ageing potentiates diet-induced glucose intolerance, β-cell failure and tissue inflammation through TLR4.

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