Adaptive Changes of the Insig1/SREBP1/SCD1 Set Point Help Adipose Tissue to Cope With Increased Storage Demands of Obesity

  1. Antonio Vidal-Puig1,14
  1. 1University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, U.K.
  2. 2Department of Biosciences, CVGI iMED, AstraZeneca Research and Development, Mölndal, Sweden
  3. 3Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany
  4. 4Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos Facultad de Ciencias de la Salud Avda.de Atenas s/n28922 Alcorcón, Madrid, Spain
  5. 5INSERM, Paul Sabatier University, UMR1048, Institute of Metabolic and Cardiovascular Diseases (I2MC), Laboratory of Obesity, Toulouse, France
  6. 6MRC Human Nutrition Research, Elsie Widdowson Laboratory & University of Cambridge, Department of Biochemistry, Cambridge, U.K.
  7. 7Hospital Virgen de la Victoria, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Malaga, Spain
  8. 8INSERM U-1060; INRA U-1235; Human Nutrition Research Center of Lyon CarMeN Laboratory, Lyon1 University, Lyon, France
  9. 9Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana
  10. 10Laboratory of Clinical Biochemistry, Toulouse, France
  11. 11Department of Medicine, Division of Internal Medicine, and Department of Psychiatry, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland
  12. 12Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición CB06/03/010, Girona, Spain
  13. 13Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
  14. 14Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.
  1. Corresponding author: Antonio Vidal-Puig, ajv22{at}medschl.cam.ac.uk.
  1. S.C. and R.M.H. contributed equally to this work.

Abstract

The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

Footnotes

  • Received December 14, 2012.
  • Accepted August 1, 2013.

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  1. Diabetes vol. 62 no. 11 3697-3708
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