Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance

EMBO Rep. 2018 Mar;19(3):e45009. doi: 10.15252/embr.201745009. Epub 2018 Feb 2.


Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPRmt on metabolism, ClpP knockout (ClpP-/-) mice were analyzed. ClpP-/- mice fed ad libitum have reduced adiposity and paradoxically improved insulin sensitivity. Absence of ClpP increased whole-body energy expenditure and markers of mitochondrial biogenesis are selectively up-regulated in the white adipose tissue (WAT) of ClpP-/- mice. When challenged with a metabolic stress such as high-fat diet, despite similar caloric intake, ClpP-/- mice are protected from diet-induced obesity, glucose intolerance, insulin resistance, and hepatic steatosis. Our results show that absence of ClpP triggers compensatory responses in mice and suggest that ClpP might be dispensable for mammalian UPRmt initiation. Thus, we made an unexpected finding that deficiency of ClpP in mice is metabolically beneficial.

Keywords: adipose tissue; caseinolytic peptidase P; insulin sensitivity; mitochondria; obesity.

Publication types

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

MeSH terms

  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Diet, High-Fat / adverse effects
  • Endopeptidase Clp / genetics*
  • Energy Metabolism / genetics
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Insulin Resistance / genetics*
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Unfolded Protein Response / genetics


  • CLPP protein, mouse
  • Endopeptidase Clp