TY - JOUR
T1 - TNFα drives mitochondrial stress in POMC neurons in obesity
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 Eduardo
AU - Jastroch, Martin
AU - Tschöp, Matthias H.
N1 - Funding Information:
C.-X.Y. is supported by an AMC fellowship and Dutch Diabetes Fonds (2015.82.1826), the Netherlands. A.G. and K.-K.C. are supported by Sonderforschungsbereich (SFB)870, Germany. J.E.S. is supported by a National Institute of Health (NIH) grant (R01 HL090948), USA. M.H.T. is supported by the Alexander von Humboldt Foundation, the Helmholtz Alliance ICEMED and the Helmholtz Initiative on Personalized Medicine iMed by Helmholtz Association, Helmholtz cross-programme topic ‘Metabolic Dysfunction’, the German Research Foundation DFG (SFB1123 & Nutripathos Project ANR-15-CE14-0030) as well as the European Research Council ERC (AdG HypoFlam no. 695054).
Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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.
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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U2 - 10.1038/ncomms15143
DO - 10.1038/ncomms15143
M3 - Article
AN - SCOPUS:85029844158
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 15143
ER -
