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Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure

Authors
  • Kwok, Albert1, 2
  • Zvetkova, Ilona1, 2
  • Virtue, Sam1, 2
  • Luijten, Ineke3
  • Huang-Doran, Isabel1, 2
  • Tomlinson, Patsy1, 2
  • Bulger, David A.1, 2
  • West, James4
  • Murfitt, Steven4
  • Griffin, Julian4, 5
  • Alam, Rafeah6
  • Hart, Daniel1, 2
  • Knox, Rachel1, 2
  • Voshol, Peter7
  • Vidal-Puig, Antonio1, 2
  • Jensen, Jørgen8
  • O'Rahilly, Stephen1, 2
  • Semple, Robert K.3, 1, 2
  • 1 The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
  • 2 MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
  • 3 Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
  • 4 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
  • 5 Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Medicine, Imperial College London, The Sir Alexander Fleming Building, London, UK
  • 6 Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
  • 7 Louis Bolk Institute, Kosterijland 3-5, NL-3981 AJ, Bunnik, the Netherlands
  • 8 Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ulleval Stadion, 0806 Oslo, Norway
Type
Published Article
Journal
Molecular Metabolism
Publisher
Elsevier BV
Publication Date
May 19, 2020
Volume
40
Identifiers
DOI: 10.1016/j.molmet.2020.101020
PMID: 32439336
PMCID: PMC7385515
Source
PubMed Central
Keywords
License
Unknown

Abstract

• SHORT syndrome features insulin resistance and reduced adiposity without dyslipidaemia and fatty liver. • A mouse model with a pathogenic human PI 3-Kinase mutation recapitulates this uncoupling. • Surprisingly, no adipose injury nor increased liver de novo lipogenesis is seen. • Energy expenditure is increased, causing resistance to diet-induced obesity. • This increases evidence for some beneficial metabolic effects of PI 3-Kinase inhibition.

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