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ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function
E R McGrath1, A Folick1,2, L J Morrissette3
1Diabetes Center, University of California, San Francisco, CA, USA.
Abstract:
Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify a distinct apolipoprotein E (ApoE)+ microglial population enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These microglia engage multiple functional programs related to lipid handling, interferon signaling, and stress responses that are differentially regulated within the ME. Consumption of a Western diet (WD) increased interferon signaling and lipid accumulation in ME microglia. Expression of the human APOE4 isoform in mice exacerbated microglial lipid dysregulation, interferon signaling, and impaired ME myelin organization. Deleting APOE in microglia attenuated their ability to couple lipid accumulation to interferon signaling, identifying microglial APOE as a cell-intrinsic determinant of interferon responses. Finally, selective activation of liver X receptor signaling using synthetic HDL nanoparticles restored microglial lipid homeostasis, improved hypothalamic leptin responsiveness, and limited weight gain in WD-fed mice. Together, these findings define an Apoe-dependent regulatory program in ME microglia that is therapeutically targetable and clarify how nutritional stress disrupts hypothalamic control of metabolic homeostasis.
Insights
Researchers discovered specialized brain microglia that regulate metabolism. Targeting apolipoprotein E (ApoE) in these cells improved metabolic homeostasis and reduced weight gain in mice fed a Western diet.
Area of Science:
- Neuroimmunology
- Metabolic regulation
- Hypothalamic function
Background:
- Microglia play a role in hypothalamic control of metabolism.
- The specific mechanisms of microglial contribution are not fully understood.
Purpose of the Study:
- To identify and characterize microglial populations involved in metabolic regulation within the hypothalamus.
- To investigate the role of apolipoprotein E (ApoE) in microglial function and metabolic homeostasis.
Main Methods:
- Identification of a distinct apolipoprotein E (ApoE) positive microglial population in the median eminence (ME).
- Analysis of microglial functional programs related to lipid handling, interferon signaling, and stress responses.
- Utilizing mouse models with human APOE isoform expression or microglial ApoE deletion.
- Employing synthetic HDL nanoparticles to activate liver X receptor signaling.
Main Results:
- ApoE+ microglia in the ME exhibit distinct functional programs, including lipid handling and interferon signaling.
- Western diet consumption increases interferon signaling and lipid accumulation in ME microglia.
- Human APOE4 expression exacerbates microglial lipid dysregulation and impairs ME myelin organization.
- Microglial ApoE is crucial for coupling lipid accumulation to interferon signaling.
- Targeting liver X receptor signaling with HDL nanoparticles restored lipid homeostasis and improved hypothalamic leptin responsiveness, limiting weight gain.
Conclusions:
- A novel ApoE-dependent regulatory program in ME microglia controls metabolic homeostasis.
- Microglial ApoE is a key determinant of interferon responses within the hypothalamus.
- Therapeutic targeting of ME microglia offers a potential strategy to address metabolic dysfunction caused by nutritional stress.
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