title: Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism.
abstract: We investigated the effects of obesity surgery-induced weight loss on transcription factor 7-like 2 gene (TCF7L2) alternative splicing in adipose tissue and liver. Furthermore, we determined the association of TCF7L2 splicing with the levels of plasma glucose and serum free fatty acids (FFAs) in three independent studies (n = 216). Expression of the short mRNA variant, lacking exons 12, 13, and 13a, decreased after weight loss in subcutaneous fat (n = 46) and liver (n = 11) and was more common in subcutaneous fat of subjects with type 2 diabetes than in subjects with normal glucose tolerance in obese individuals (n = 54) and a population-based sample (n = 49). Additionally, there was a positive correlation between this variant and the level of fasting glucose in nondiabetic individuals (n = 113). This association between TCF7L2 splicing and plasma glucose was independent of the TCF7L2 genotype. Finally, this variant was associated with high levels of serum FFAs during hyperinsulinemia, suggesting impaired insulin action in adipose tissue, whereas no association with insulin secretion or insulin-stimulated whole-body glucose uptake was observed. Our study shows that the short TCF7L2 mRNA variant in subcutaneous fat is regulated by weight loss and is associated with hyperglycemia and impaired insulin action in adipose tissue.
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.forename: Tiina
authors.initials: T
authors.lastname: Kuulasmaa
authors.forename: Sari
authors.initials: S
authors.lastname: Venesmaa
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.forename: Maija
authors.initials: M
authors.lastname: Vaittinen
authors.forename: Leena
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: Matti
authors.initials: M
authors.lastname: Pääkkönen
authors.forename: Helena
authors.initials: H
authors.lastname: Gylling
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D017398:Alternative Splicing; D001706:Biopsy; D001786:Blood Glucose / Q000032:analysis*; D015992:Body Mass Index; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D015390:Gastric Bypass; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism / Q000473:pathology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D012333:RNA, Messenger; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein