Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to…

• AD
  American Diabetes Association

  Awards: R01DK125820, P30DK063491, R01DK126944, 1-18-PDF-094, R01DK124496
• LL
  Larry L. Hillblom Foundation
• HU
  Harvard University
• KI
  Karolinska Institutet
• NN
  Novo Nordisk
• SL
  Stockholms Läns Landsting
• V
  Vetenskapsrådet
• NS
  NOMIS Stiftung
• NI
  National Institutes of Health

  Awards: R01DK125820, R01DK122804, R01DK124496, 2P30CA023100, S10OD023527, R01DK126944, P30DK063491
• UO
  University of California, San Diego

  Awards: R01DK125820, SCR_022039, P30DK063491
• CF
  Center for Innovative Medicine
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases

  Awards: R01DK125820, R01DK128796, R01DK122804, R01DK124496, R01DK126944, R00HL143277, R01DK057978, P30DK063491