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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: 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. 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. Methods: Male 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. Results: We 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. Conclusions: Hyperglycemia 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.

Original languageEnglish
Article number293
Number of pages13
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
Publication statusPublished - 22 Oct 2018

Keywords

  • Astrocytes
  • High-fat feeding
  • Hippocampus
  • Hyperglycemia
  • Microglia
  • Neuroinflammation
  • Streptozotocin

Cite this

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title = "Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation",
abstract = "Background: 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. 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. Methods: Male 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. Results: We 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. Conclusions: Hyperglycemia 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.",
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Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation. / Wanrooy, Brooke J.; Kumar, Kathryn Prame; Wen, Shu Wen; Qin, Cheng Xue; Ritchie, Rebecca H.; Wong, Connie H.Y.

In: Journal of Neuroinflammation, Vol. 15, No. 1, 293, 22.10.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation

AU - Wanrooy, Brooke J.

AU - Kumar, Kathryn Prame

AU - Wen, Shu Wen

AU - Qin, Cheng Xue

AU - Ritchie, Rebecca H.

AU - Wong, Connie H.Y.

PY - 2018/10/22

Y1 - 2018/10/22

N2 - Background: 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. 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. Methods: Male 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. Results: We 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. Conclusions: Hyperglycemia 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.

AB - Background: 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. 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. Methods: Male 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. Results: We 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. Conclusions: Hyperglycemia 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.

KW - Astrocytes

KW - High-fat feeding

KW - Hippocampus

KW - Hyperglycemia

KW - Microglia

KW - Neuroinflammation

KW - Streptozotocin

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U2 - 10.1186/s12974-018-1329-8

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M3 - Article

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JO - Journal of Neuroinflammation

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SN - 1742-2094

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