TNFα drives mitochondrial stress in POMC neurons in obesity

Nat Commun. 2017 May 10:8:15143. doi: 10.1038/ncomms15143.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Electron Transport Complex I / genetics
  • Gene Expression Regulation
  • Hypothalamus, Middle / metabolism*
  • Mice
  • Microglia / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics
  • Neurites / metabolism
  • Neurons / metabolism*
  • Obesity / metabolism*
  • Pro-Opiomelanocortin*
  • RANK Ligand / genetics
  • Signal Transduction
  • Stress, Physiological*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Pro-Opiomelanocortin
  • Adenosine Triphosphate
  • Electron Transport Complex I