Regulation and function of FTO mRNA expression in human skeletal muscle and subcutaneous adipose tissue.
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.


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 PGC1alpha.


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.
Grunnet
Louise G
LG
Steno Diabetes Center, Gentofte, Denmark.
Nilsson
Emma
E
Ling
Charlotte
C
Hansen
Torben
T
Pedersen
Oluf
O
Groop
Leif
L
Vaag
Allan
A
Poulsen
Pernille
P
D000273:Adipose Tissue / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000235:genetics; D010085:Oxidative Phosphorylation; D011110:Polymorphism, Genetic; D011506:Proteins / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values
D007328:Insulin; D011506:Proteins; D012333:RNA, Messenger; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human