Regulation and Function of FTO mRNA Expression in Human Skeletal Muscle and Subcutaneous Adipose Tissue

  1. Louise G. Grunnet1,2,
  2. Emma Nilsson1,
  3. Charlotte Ling3,
  4. Torben Hansen1,
  5. Oluf Pedersen1,
  6. Leif Groop3,
  7. Allan Vaag1 and
  8. Pernille Poulsen1
  1. 1Steno Diabetes Center, Gentofte, Denmark;
  2. 2Department of International Health, University of Copenhagen, Copenhagen, Denmark;
  3. 3Department of Clinical Sciences, Diabetes and Endocrinology, Malmø University Hospital, Malmø, Sweden.
  1. Corresponding author: Pernille Poulsen, pepn{at}novonordisk.com.

Abstract

OBJECTIVE Common variants in FTO (the fat mass– and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism.

RESEARCH DESIGN AND METHODS The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62–83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25–32 years) and elderly (58–66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158).

RESULTS Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1α.

CONCLUSIONS The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 12, 2009.
    • Accepted June 29, 2009.
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  1. Diabetes vol. 58 no. 10 2402-2408
  1. All Versions of this Article:
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