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Targeted PPARδ activation reprograms microglial immunometabolism and improves insulin sensitivity in HFD-fed rats
Han Jiao1, Fernando Cázarez-Márquez2, Valentina Sophia Rumanova1
1Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam, The Netherlands; Department of Clinical Chemistry, Laboratory of Endocrinology, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Targeting microglial lipid metabolism with PPARδ agonists improves immune function and hypothalamic health in obesity. This approach enhances microglial activity and insulin sensitivity, offering a potential therapeutic strategy for metabolic disorders.
Area of Science:
- Neuroimmunology
- Metabolic Disease Research
- Pharmacology
Background:
- Microglia lipid metabolism is vital for immune function and neuronal health.
- High-fat diets disrupt microglial lipid processing, impairing neuroimmunity and exacerbating obesity.
- The potential of enhancing microglial lipid metabolism to counter obesity-related hypothalamic dysfunction is unexplored.
Purpose of the Study:
- To investigate if activating peroxisome proliferator-activated receptor delta (PPARδ) can restore microglial immune function and mitigate hypothalamic dysfunction in obesity.
- To identify potent PPARδ agonists for therapeutic intervention.
Main Methods:
- Utilized thermal proteome profiling to identify GW0742 as a potent PPARδ agonist.
- Treated microglial cells in vitro with GW0742 to assess effects on phagocytosis, inflammation, and metabolic flexibility.
- Administered GW0742 via nanoparticles (NPs-GW0742) to mediobasal hypothalamic microglia in high-fat diet-fed rats.
Main Results:
- In vitro, GW0742 enhanced microglial phagocytosis, reduced inflammation, and improved metabolic flexibility.
- In vivo, targeted delivery of NPs-GW0742 reprogrammed hypothalamic microglial activity.
- This intervention improved insulin sensitivity without altering body weight or food intake.
Conclusions:
- Activating microglial PPARδ metabolism offers a direct central metabolic benefit.
- Targeting microglial lipid metabolism presents a promising therapeutic strategy for improving metabolic health in obesity and associated hypothalamic dysfunction.
