High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8714-9. doi: 10.1073/pnas.1509930112. Epub 2015 Jun 29.


Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

Keywords: FGF21; brown fat; mitochondria; polymerase gamma; thermogenesis.

Publication types

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

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Aerobiosis
  • Animals
  • Diet, High-Fat*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Fibroblast Growth Factors / physiology*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / metabolism
  • Thermogenesis / genetics*


  • fibroblast growth factor 21
  • Fibroblast Growth Factors

Associated data

  • SRA/SRP057650