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

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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1329-8) contains supplementary material, which is available to authorized users.

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy

“…Several reviews have summarised common features of animal models of diabetic cardiomyopathy (Hsueh et al, 2007; Bugger and Abel, 2009), and the Diabetic Complications Consortium provides validation criteria for animal studies of diabetes-induced complications. More recently, several laboratories have devised protocols that use a dietary intervention superimposed on the pancreatic toxin, STZ, to induce T2DM (Barrière et al, 2018; Wanrooy et al, 2018). This model exhibits diastolic dysfunction comparable to the db/db mouse but with a milder systemic phenotype, more closely resembling the progression of systemic metabolic changes observed in humans with T2DM, including progressive gains in body weight and fat mass.…”

“…Although this model does not mimic the more clinically prevalent T2DM, the STZ model avoids confounding factors including obesity and impaired leptin signalling which need to be taken into account in common genetic models of T2DM, including spontaneously diabetic db/db and ob/ob mice. Recently, there has been an emergence of T2DM models incorporating low-dose STZ alongside dietary intervention, as high-fat diet alone is not enough to induce diabetes (Barrière et al, 2018; Wanrooy et al, 2018). Notably, the use of low-dose STZ and high fat diet in a rat model replicates late-stage clinical T2DM where β-cell loss is apparent (Butler et al, 2003).…”

Downregulation of Astrocytic Kir4.1 Potassium Channels Is Associated with Hippocampal Neuronal Hyperexcitability in Type 2 Diabetic Mice

“…Furthermore, among the effects of hyperglycemia seen in glial cells, It has been shown that GFAP immunoreactivity increases in the hippocampus of streptozotocin treated mice [47]. In addition, there is an increase in the numbers of GFAP + Müller cells in the retina of db/db mice as compared with non-diabetic controls [48].…”

Effect of Hypoproteic and High-Fat Diets on Hippocampal Blood-Brain Barrier Permeability and Oxidative Stress

“…Further, the same authors concluded that HFD triggers neuroinflammation, as evaluated by reactive microglia and release of pro-inflammatory cytokines (40). Moreover, in an animal model of HFD for 9 weeks, an increase in leukocyte transmigration into the brain parenchyma was observed (41). Accordingly, in the present study we showed a downregulation of collagen IV, the most important protein of the BBB basement membrane, and the tight junction protein, claudin-5, which is strong indicator of BBB dysfunction.…”