Dataset Information

Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1.

ABSTRACT:

Objective

The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD).

Methods

C57BL/6J wild-type, Cx3cr1^-/- , Ccr2^-/- , and Cx3cr1^-/- Ccr2^-/- double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age.

Results

All groups gained weight at a similar rate and developed a similar degree of adiposity, hyperglycemia, glucose intolerance, and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2^-/- and Cx3cr1^-/- Ccr2^-/- mice but not in Cx3cr1^-/- mice. Flow cytometric analysis of perigonadal adipose tissue of male, but not female, mice revealed trends to lower CD11c+MGL1- M1-like macrophages and higher CD11c-MGL1+?M2-like macrophages as a percentage of CD45+F4/80+CD11b+?macrophages in Cx3cr1^-/- Ccr2^-/- mice versus wild-type mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes.

Conclusions

Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence the metabolic effects of a 45% HFD-induced obesity in these model conditions.

SUBMITTER: Zhang H

PROVIDER: S-EPMC5610963 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1.

Zhang Hanrui H Hinkle Christine C CC O'Neill Sean M SM Shi Jianting J Caughey Jennifer J Lynch Emma E Lynch Gina G Gerelus Mark M Tsai Andrew S D ASD Shah Rachana R Ferguson Jane F JF Ahima Rexford S RS Reilly Muredach P MP

Obesity (Silver Spring, Md.) 20170626 8

<h4>Objective</h4>The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD).<h4>Methods</h4>C57BL/6J wild-type, Cx3cr1<sup>-/-</sup> , Ccr2<sup>-/-</sup> , and Cx3cr1<sup>-/-</sup> Ccr2<sup>-/-</sup> double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age.<h4>Results</h4>All ...[more]

PMID: 28650582

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Project description: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.

Dataset Information

Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1.

Objective

Methods

Results

Conclusions

Publications

Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1.

Similar Datasets

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