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Transducin-like enhancer of split 3 (TLE3) in adipose tissue is increased in situations characterized by decreased PPARγ gene expression

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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.

Key message

  • 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.

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Acknowledgments

We greatly appreciate the technical assistance of Isabel Alonso, Oscar Rovira and Emili LosHuertos (Unit of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona, Hospital Universitari de Girona Dr. Josep Trueta). This study was supported by the Spanish Ministry of Science and Innovation (FIS 2011–00214) and CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn). The CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative from the Instituto de Salud Carlos III (ISCIII).

Disclosures

The authors have nothing to disclose.

Author contribution

All authors of this manuscript have directly participated in the execution and analysis of the study. FJO and MS designed the study, analyzed the biochemical variables, performed the statistical analysis, and wrote the manuscript. JMM-N, MG-S, and MS analyzed biochemical variables. JIR-H, GX, and WR obtained the samples, anthropometrical characteristics, and the written consent of participants. SR-C and AV-P provided samples from HFD and PPARγ2-KO mouse models. BP and AV-P provided important intellectual content. JMF-R carried out the conception and coordination of this study and helped with the writing of this manuscript.

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Authors and Affiliations

  1. 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

    Francisco José Ortega, Marta Serrano, José María Moreno-Navarrete, Mònica Sabater, Gemma Xifra, Wifredo Ricart & José Manuel Fernández-Real

  2. Department of Clinical Biochemistry, Metabolic Research Laboratories, Institute of Metabolic Science, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Sergio Rodriguez-Cuenca & Antonio Vidal-Puig

  3. Instituto de Investigaciones Biomédicas ‘Alberto Sols’ de Madrid (IIBM), Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain

    María Gómez-Serrano & Belén Peral

  4. Department of Surgery, Institut d’Investigació Biomèdica de Girona (IdIBGi), Girona, Spain

    Jose Ignacio Rodriguez-Hermosa

Authors
  1. Francisco José Ortega
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  2. Marta Serrano
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  3. Sergio Rodriguez-Cuenca
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  4. José María Moreno-Navarrete
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  6. Mònica Sabater
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  7. Jose Ignacio Rodriguez-Hermosa
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  8. Gemma Xifra
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  9. Wifredo Ricart
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  10. Belén Peral
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  11. Antonio Vidal-Puig
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  12. José Manuel Fernández-Real
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Corresponding authors

Correspondence to Francisco José Ortega or José Manuel Fernández-Real.

Additional information

Francisco José Ortega and Marta Serrano contributed equally to this manuscript.

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Ortega, F.J., Serrano, M., Rodriguez-Cuenca, S. et al. Transducin-like enhancer of split 3 (TLE3) in adipose tissue is increased in situations characterized by decreased PPARγ gene expression. J Mol Med 93, 83–92 (2015). https://doi.org/10.1007/s00109-014-1207-5

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  • DOI: https://doi.org/10.1007/s00109-014-1207-5

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