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

5 years ago

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

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

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. Mitochondrial matrix protease ClpP is proposed to play an important role in the initiation of mammalian mitochondrial unfolded protein response (UPRmt). This study reveals that ClpP deficiency in mice has paradoxical beneficial effects on metabolism and ClpP might be dispensable for mammalian UPRmt initiation.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/embr.201745009