Rosiglitazone Increases Indexes of Stearoyl-CoA Desaturase Activity in Humans

Link to Insulin Sensitization and the Role of Dominant-Negative Mutation in Peroxisome Proliferator-Activated Receptor-γ

  1. Ulf Risérus1,
  2. Garry D. Tan1,
  3. Barbara A. Fielding1,
  4. Matt J. Neville1,
  5. Jenny Currie1,
  6. David B. Savage2,
  7. V. Krishna Chatterjee2,
  8. Keith N. Frayn1,
  9. Stephen O’Rahilly2 and
  10. Fredrik Karpe1
  1. 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, U.K
  2. 2Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, U.K
  1. Address correspondence and reprint requests to Dr. Ulf Risérus, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LJ, U.K. E-mail: ulf.riserus{at}oxlip.ox.ac.uk. or fredrik.karpe{at}academ.ox.ac.uk

Abstract

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-γ (PPARγ) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and Δ6- and Δ5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and Δ5-desaturase but not Δ6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARγ carrier, SCD and Δ5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARγ mutation supports a pivotal role of PPARγ function in SCD regulation.

Footnotes

  • S.O. has been a member of an advisory panel for Prosidion, Biovitrum, Cambridge Antibody Technology, Cambridge Biotechnology, Paradigm Therapeutics, and Xcellsyz; holds stock in Prosidion and Biovitrum; and has received honoraria from Merck and Unilever.

    • Accepted February 3, 2005.
    • Received November 18, 2004.
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