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

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

Author information

1
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
2
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
3
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
5
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA deepa-sathyaseelan@ouhsc.edu.

Abstract

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

PMID:
29420235
PMCID:
PMC5836096
DOI:
10.15252/embr.201745009
[Indexed for MEDLINE]
Free PMC Article

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