Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

Diabetologia. 2015 Oct;58(10):2371-80. doi: 10.1007/s00125-015-3704-7. Epub 2015 Aug 2.

Abstract

Aim/hypothesis: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication.

Methods: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice).

Results: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response.

Conclusions/interpretation: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

Keywords: DRP1; ER stress; FGF 21; Mitochondrial dynamics; Mitochondria–ER juxtaposition structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Adiposity / genetics
  • Animals
  • Diet, High-Fat
  • Dynamins / genetics
  • Dynamins / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Energy Metabolism / genetics
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Liver / metabolism*
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / genetics*
  • Obesity / genetics
  • Obesity / metabolism*

Substances

  • fibroblast growth factor 21
  • Activating Transcription Factor 4
  • Fibroblast Growth Factors
  • Dnm1l protein, mouse
  • Dynamins

Associated data

  • GEO/GSE64222