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Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding
Jung Dae Kim1, Nal Ae Yoon1, Sungho Jin1
1Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after high-fat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microglia activation is ill defined. Here, we show that in vivo, HFD induced a rapid and transient increase in uncoupling protein 2 (Ucp2) mRNA expression together with changes in mitochondrial dynamics. Selective microglial deletion of Ucp2 prevented changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation. In association with these, male and female mice were protected from HFD-induced obesity, showing decreased feeding and increased energy expenditure that were associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. Together, our data point to a fuel-availability-driven mitochondrial mechanism as a major player of microglia activation in the central regulation of DIO.
Insights
Diet-induced obesity rapidly activates microglia via mitochondrial changes. Blocking uncoupling protein 2 (Ucp2) in microglia prevents obesity and hypothalamic inflammation, revealing a key mechanism.
Area of Science:
- Neuroimmunology
- Metabolic disease research
- Mitochondrial biology
Background:
- Microglia are central to brain immune responses and inflammation.
- Diet-induced obesity (DIO) causes rapid microglia activation and hypothalamic inflammation, preceding weight gain.
- The intracellular pathways driving this microglia activation remain unclear.
Purpose of the Study:
- To investigate the intracellular mechanisms of microglia activation in diet-induced obesity.
- To determine the role of uncoupling protein 2 (Ucp2) in HFD-induced microglia activation and DIO.
Main Methods:
- Utilized mouse models with selective microglial deletion of Ucp2.
- Administered high-fat diet (HFD) to induce obesity.
- Assessed microglia activation, mitochondrial dynamics, hypothalamic inflammation, feeding behavior, and energy expenditure.
Main Results:
- HFD rapidly increased Ucp2 mRNA and altered mitochondrial dynamics in microglia.
- Selective microglial Ucp2 deletion prevented mitochondrial dysfunction, microglia activation, and hypothalamic inflammation.
- Mice lacking microglial Ucp2 were protected from DIO, exhibiting reduced feeding and increased energy expenditure.
Conclusions:
- Mitochondrial mechanisms, specifically involving Ucp2, are critical for microglia activation in DIO.
- Targeting microglial Ucp2 offers a potential strategy for treating obesity and related metabolic disorders.
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