Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation

Brooke J Wanrooy,Kathryn Prame Kumar,Rebecca H Ritchie,Connie H Y Wong,Shu Wen Wen,Cheng Xue Qin

doi:10.1186/s12974-018-1329-8

Abstract

BackgroundHigh-fat feeding and hyperglycemia, key risk factors for the development of metabolic syndrome (MetS), are emerging to associate with increased risk of developing dementia and cognitive decline. Despite this, clinical and experimental studies have yet to elucidate the specific contributions of either high-fat feeding or hyperglycemia to potential neuroinflammatory components. In this study, we delineate these individual components of MetS in the development of neuroinflammation.MethodsMale C57Bl/6 J adult mice were treated with either citrate vehicle (CIT) or streptozotocin (STZ; 55 mg/kg) 3, 5 and 7 days before commencement of either a normal or high-fat diet for 9 or 18 weeks. By creating separate models of high-fat feeding, STZ-induced hyperglycemia, as well as in combination, we were able to delineate the specific effects of a high-fat diet and hyperglycemia on the brain. Throughout the feeding regime, we measured the animals’ body weight and fasting blood glucose levels. At the experimental endpoint, we assessed plasma levels of insulin, glycated haemoglobin and performed glucose tolerance testing. In addition, we examined the effect of high fat-feeding and hyperglycemia on the levels of systemic inflammatory cytokines, gliosis in the hippocampus and immune infiltration in cerebral hemispheric tissue. Furthermore, we used intravital multiphoton microscopy to assess leukocyte-endothelial cell interactions in the cerebral vasculature of mice in vivo.ResultsWe showed that acute hyperglycemia induces regional-specific effects on the brain by elevating microglial numbers and promotes astrocytosis in the hippocampus. In addition, we demonstrated that chronic hyperglycemia supported the recruitment of peripheral GR1+ granulocytes to the cerebral microvasculature in vivo. Moreover, we provided evidence that these changes were independent of the systemic inflammation associated with high-fat feeding.ConclusionsHyperglycemia alone preferentially induces microglial numbers and astrocytosis in the hippocampus and is associated with the peripheral recruitment of leukocytes to the cerebrovasculature, but not systemic inflammation. High-fat feeding alone, and in combination with hyperglycemia, increases the systemic pro-inflammatory cytokine milieu but does not result in brain-specific immune gliosis. These results shed light on the specific contributions of high-fat feeding and hyperglycemia as key factors of MetS in the development of neuroinflammation.

Highlights

High-fat feeding and hyperglycemia, key risk factors for the development of metabolic syndrome (MetS), are emerging to associate with increased risk of developing dementia and cognitive decline
We show that mice on a high-fat diet (HFD) (CIT + HFD) exhibited significant weight gain compared to mice fed on a control diet (CIT + CON) as confirmed by the area under the curve (AUC) (Fig. 1a, b)
Our findings show that mice in the citrate vehicle (CIT) + HFD and STZ + HFD groups had increased levels of systemic pro-inflammatory IL-6 after 18 weeks, but not STZ + CON mice, suggesting that high-fat feeding is more likely to contribute to systemic inflammation over hyperglycemia

Summary

Introduction

High-fat feeding and hyperglycemia, key risk factors for the development of metabolic syndrome (MetS), are emerging to associate with increased risk of developing dementia and cognitive decline. Clinical and experimental studies have yet to elucidate the specific contributions of either high-fat feeding or hyperglycemia to potential neuroinflammatory components. We delineate these individual components of MetS in the development of neuroinflammation. The prevalence of metabolic syndrome (MetS) in adults is increasing worldwide [1], largely due to several factors such as ageing of the population, increased life expectancy and chronic overnutrition and physical inactivity [2]. Obesity is emerging as a major health concern owing to its key role in MetS and being a well-recognised risk factor for the development of type 2 diabetes (T2D) and related cardiovascular diseases (CVDs) [3]. Clinical studies demonstrate that patients with T2D are more susceptible to symptoms of neurological impairment, but how T2D may induce neurological deficits remains undetermined

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