title: Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss.
abstract: OBJECTIVE
  The insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue.
  
  
  METHODS
  To determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49).
  
  
  RESULTS
  Expression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10(-5)) and the VLCD (p = 1 × 10(-4)). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10(-22)). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10(-5)), a known regulator of INSR exon 11 splicing.
  
  
  CONCLUSIONS
  INSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70210, Kuopio, Finland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.forename: Maija
authors.initials: M
authors.lastname: Hämäläinen
authors.forename: Henna
authors.initials: H
authors.lastname: Cederberg
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.forename: Sari
authors.initials: S
authors.lastname: Venesmaa
authors.forename: Pekka
authors.initials: P
authors.lastname: Miettinen
authors.forename: Imre
authors.initials: I
authors.lastname: Ilves
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Herzig
authors.forename: Marjukka
authors.initials: M
authors.lastname: Kolehmainen
authors.forename: Leila
authors.initials: L
authors.lastname: Karhunen
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
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: D000273:Adipose Tissue / Q000378:metabolism*; D017398:Alternative Splicing; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D050110:Bariatric Surgery; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D031204:Caloric Restriction; D004038:Diet, Reducing; D019075:Electrophoresis, Capillary; D005215:Fasting; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss
chemical_list: D015703:Antigens, CD; D001786:Blood Glucose; D007328:Insulin; C435941:INSR protein, human; D011972:Receptor, Insulin