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

Shylesh Bhaskaran, Gavin Pharaoh, Rojina Ranjit, Ashley Murphy, Satoshi Matsuzaki, Binoj C. Nair, Brittany Forbes, Suzana Gispert, Georg Auburger, Kenneth M. Humphries, Michael Kinter, Timothy M. Griffin, Sathyaseelan S. Deepa

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Article numbere45009
JournalEMBO Reports
Issue number3
StatePublished - Mar 2018


  • adipose tissue
  • caseinolytic peptidase P
  • insulin sensitivity
  • mitochondria
  • obesity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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