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Article

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, View ORCID ProfileSathyaseelan S Deepa
DOI 10.15252/embr.201745009 | Published online 02.02.2018
EMBO reports (2018) e45009
Shylesh Bhaskaran
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Gavin Pharaoh
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USADepartment of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Rojina Ranjit
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Ashley Murphy
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Satoshi Matsuzaki
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Binoj C Nair
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Brittany Forbes
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Suzana Gispert
Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany
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Georg Auburger
Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany
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Kenneth M Humphries
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Michael Kinter
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Timothy M Griffin
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Sathyaseelan S Deepa
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Author Affiliations

  1. Shylesh Bhaskaran1,
  2. Gavin Pharaoh1,2,
  3. Rojina Ranjit1,
  4. Ashley Murphy1,
  5. Satoshi Matsuzaki1,
  6. Binoj C Nair3,
  7. Brittany Forbes1,
  8. Suzana Gispert4,
  9. Georg Auburger4,
  10. Kenneth M Humphries1,
  11. Michael Kinter1,
  12. Timothy M Griffin1 and
  13. Sathyaseelan S Deepa (deepa-sathyaseelan{at}ouhsc.edu)*,1,5
  1. 1Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
  2. 2Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  3. 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  4. 4Experimental Neurology, Goethe University Medical School, Frankfurt am Main, Germany
  5. 5Present Address: Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  1. ↵*Corresponding author. Tel: +1 405 271 2633; E‐mail: deepa-sathyaseelan{at}ouhsc.edu
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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.

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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.

  • ClpP−/− mice have reduced adiposity and improved insulin sensitivity.

  • Mitochondrial biogenesis markers and respiration are selectively up‐regulated in white adipose tissue of ClpP−/− mice.

  • ClpP−/− mice are protected from diet‐induced obesity, glucose intolerance, and insulin resistance.

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

EMBO Reports (2018) e45009

  • Received August 14, 2017.
  • Revision received December 8, 2017.
  • Accepted December 22, 2017.
  • © 2018 The Authors
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Volume 19, Issue 4
01 April 2018 | pp -
EMBO reports: 19 (4)
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