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TNFα drives mitochondrial stress in POMC neurons in obesity
Chun-Xia Yi1,2, Marc Walter1, Yuanqing Gao1
1Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Division of Metabolic Diseases, Department of Medicine, Technische Universität München, German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
Abstract:
Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity.
Insights
A high-calorie diet activates brain immune cells (microglia) that release TNFα, disrupting appetite control neurons (POMC) and leading to obesity. Targeting TNFα downstream signals reverses these effects, offering a potential obesity treatment.
Area of Science:
- Neuroimmunology
- Metabolic Neuroscience
- Cellular Metabolism
Background:
- Hypercaloric diets induce obesity and alter hypothalamic function.
- Microglial activation in the mediobasal hypothalamus (MBH) is linked to obesity, but its causal role in pro-opiomelanocortin (POMC) neuron dysfunction is unclear.
Purpose of the Study:
- To investigate the causal link between microglial activation and POMC neuron dysfunction in diet-induced obesity.
- To elucidate the molecular mechanisms by which microglia influence POMC neuron activity and contribute to obesity.
Main Methods:
- Utilized diet-induced obesity mouse models.
- Investigated microglial reactivity and TNFα secretion in the MBH.
- Analyzed mitochondrial function and neuronal excitability in POMC neurons.
- Disrupted gene expression of TNFα downstream targets (TNFSF11A, NDUFAB1) in the MBH.
Main Results:
- Hypercaloric diet-induced obesity is associated with persistently activated MBH microglia that hypersecrete TNFα.
- TNFα stimulates mitochondrial ATP production and promotes mitochondrial fusion in POMC neurons, increasing their firing rate and excitability.
- Disrupting TNFSF11A or NDUFAB1 gene expression in the MBH reversed mitochondrial changes and reduced obesity.
Conclusions:
- Persistent microglial reactivity and TNFα secretion in the MBH contribute to POMC neuron mitochondrial stress and dysfunction in diet-induced obesity.
- Targeting TNFα downstream signaling pathways represents a potential therapeutic strategy for obesity.
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