TNFα drives mitochondrial stress in POMC neurons in obesity

Chun-Xia Yi, Marc Walter, Yuanqing Gao, Soledad Pitra, Beata Legutko, Stefanie Kälin, Clarita Layritz, Cristina García-Cáceres, Maximilian Bielohuby, Martin Bidlingmaier, Stephen C. Woods, Alexander Ghanem, Karl-Klaus Conzelmann, Javier E. Stern, Martin Jastroch and Matthias H. Tschöp ()
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Chun-Xia Yi: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Marc Walter: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Yuanqing Gao: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Soledad Pitra: Augusta University
Beata Legutko: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Stefanie Kälin: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Clarita Layritz: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Cristina García-Cáceres: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Maximilian Bielohuby: Endocrine Research Unit, Klinikum der Ludwig-Maximilians-Universität
Martin Bidlingmaier: Endocrine Research Unit, Klinikum der Ludwig-Maximilians-Universität
Stephen C. Woods: University of Cincinnati
Alexander Ghanem: Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians-Universität
Karl-Klaus Conzelmann: Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians-Universität
Javier E. Stern: Augusta University
Martin Jastroch: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)
Matthias H. Tschöp: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Technische Universität München, German Center for Diabetes Research (DZD)

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15143

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