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; Matthias H. Tschöp

doi:10.1038/ncomms15143

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, Matthias H. Tschöp

Medicine and Health

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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.

Original language	English
Article number	15143
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15143
State	Published - 2017

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Yi, C. X., Walter, M., Gao, Y., Pitra, S., Legutko, B., Kälin, S., Layritz, C., García-Cáceres, C., Bielohuby, M., Bidlingmaier, M., Woods, S. C., Ghanem, A., Conzelmann, K. K., Stern, J. E., Jastroch, M., & Tschöp, M. H. (2017). TNFα drives mitochondrial stress in POMC neurons in obesity. Nature Communications, 8, Article 15143. https://doi.org/10.1038/ncomms15143

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title = "TNFα drives mitochondrial stress in POMC neurons in obesity",

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.",

author = "Yi, {Chun Xia} and Marc Walter and Yuanqing Gao and Soledad Pitra and Beata Legutko and Stefanie K{\"a}lin and Clarita Layritz and Cristina Garc{\'i}a-C{\'a}ceres and Maximilian Bielohuby and Martin Bidlingmaier and Woods, {Stephen C.} and Alexander Ghanem and Conzelmann, {Karl Klaus} and Stern, {Javier E.} and Martin Jastroch and Tsch{\"o}p, {Matthias H.}",

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year = "2017",

doi = "10.1038/ncomms15143",

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AU - Yi, Chun Xia

AU - Walter, Marc

AU - Gao, Yuanqing

AU - Pitra, Soledad

AU - Legutko, Beata

AU - Kälin, Stefanie

AU - Layritz, Clarita

AU - García-Cáceres, Cristina

AU - Bielohuby, Maximilian

AU - Bidlingmaier, Martin

AU - Woods, Stephen C.

AU - Ghanem, Alexander

AU - Conzelmann, Karl Klaus

AU - Stern, Javier E.

AU - Jastroch, Martin

AU - Tschöp, Matthias H.

PY - 2017

Y1 - 2017

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AB - 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.

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SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

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TNFα drives mitochondrial stress in POMC neurons in obesity

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