title: Transducin-like enhancer of split 3 (TLE3) in adipose tissue is increased in situations characterized by decreased PPARγ gene expression.
abstract: Transgenic overexpression of adipose tissue (AT) transducin-like enhancer of split 3 (TLE3) mimicked peroxisome proliferator-activated receptor gamma (PPARγ) agonists, improving insulin resistance in mice. This study aimed to investigate TLE3 gene expression (qRT-PCR) and protein (Western blot) in subjects with a wide spectrum of obesity and insulin sensitivity and in an independent cohort of obese subjects following surgery-induced weight loss. TLE3 was analyzed in human adipocytes and after treatment with rosiglitazone. Given the findings in humans, TLE3 was also investigated in mice after a high-fat diet (HFD) and in PPARγ knockout mice. Subcutaneous (SC) AT TLE3 was increased in subjects with type 2 diabetes (T2D). In fact, SC TLE3 was associated with increased fasting glucose (r = 0.25, p = 0.015) and S6K1 activity (r = 0.671, p = 0.003), and with decreased Glut4 (r = -0.426, p = 0.006) and IRS-1 expression (-31 %, p = 0.007) and activation (P-IRS-1/IRS-1, -17 %, p = 0.024). TLE3 was preferentially expressed in mature adipocytes and increased during in vitro differentiation in parallel to PPARγ. Weight loss led to improved insulin sensitivity, increased AT PPARγ and decreased TLE3 (-24 %, p = 0.0002), while rosiglitazone administration downregulated TLE3 gene expression in fully differentiated adipocytes (-45 %, p < 0.0001). The concept that TLE3 may act as a homeostatic linchpin in AT was also supported by its increased expression in HFD-fed mice (39 %, p = 0.013) and PPARγ knockout (74 %, p = 0.001). In summary, increased AT TLE3 in subjects with T2D and in AT from HFD-fed and PPARγ knockout mice suggest that TLE3 may play an adaptive regulatory role that improves AT function under decreased PPARγ expression.
  
  
  CONCLUSIONS
  TLE3 is expressed in mature adipocytes concomitantly with PPARγ. Subcutaneous adipose TLE3 is increased in T2D patients. Adipose TLE3 is upregulated in genetically ablated PPARγ and HFD-fed mice. TLE3 may be a homeostatic linchpin in insulin resistance and defective PPARγ.
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition (UDEN), Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBERobn (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Carretera de França s/n, 17007, Girona, Spain, faloides@hotmail.com.
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Ortega
authors.forename: Marta
authors.initials: M
authors.lastname: Serrano
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez-Cuenca
authors.forename: José María
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Serrano
authors.forename: Mònica
authors.initials: M
authors.lastname: Sabater
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Hermosa
authors.forename: Gemma
authors.initials: G
authors.lastname: Xifra
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
authors.forename: Belén
authors.initials: B
authors.lastname: Peral
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D015870:Gene Expression; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; C570667:TLE3 protein, human