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Caveolar targeting links Kv1.3 with the insulin-dependent adipocyte physiology

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Abstract

The voltage-dependent potassium channel Kv1.3 participates in peripheral insulin sensitivity. Genetic ablation of Kv1.3 triggers resistance to diet-induced weight gain, thereby pointing to this protein as a pharmacological target for obesity and associated type II diabetes. However, this role is under intense debate because Kv1.3 expression in adipose tissue raises controversy. We demonstrated that Kv1.3 is expressed in white adipose tissue from humans and rodents. Moreover, other channels, such as Kv1.1, Kv1.2, Kv1.4 and especially Kv1.5, from the same Shaker family are also present. Although elevated insulin levels and adipogenesis remodel the Kv phenotype, which could lead to multiple heteromeric complexes, Kv1.3 markedly participates in the insulin-dependent regulation of glucose uptake in mature adipocytes. Adipocyte differentiation increased the expression of Kv1.3, which is targeted to caveolae by molecular interactions with caveolin 1. Using a caveolin 1-deficient 3T3-L1 adipocyte cell line, we demonstrated that the localization of Kv1.3 in caveolar raft structures is important for proper insulin signaling. Insulin-dependent phosphorylation of the channel occurs at the onset of insulin-mediated signaling. However, when Kv1.3 was spatially outside of these lipid microdomains, impaired phosphorylation was exhibited. Our data shed light on the putative role of Kv1.3 in weight gain and insulin-dependent responses contributing to knowledge about adipocyte physiology.

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Acknowledgements

Supported by the Ministerio de Economia y Competitividad (MINECO, Spain) Grants (BFU2014-54928-R and BFU2017-87104-R) and Fondo Europeo de Desarrollo Regional (FEDER). MPV and JC contributed equally and hold fellowships from the MINECO and the Fundación Tatiana Pérez de Guzmán el Bueno, respectively. Authors thank Dr. C. López-Iglesias (CCiTUB, Universitat de Barcelona) for her help in electronic Microscopy and to Dr. J. Peinado-Onsurbe for the access to human samples. The English editorial assistance of the American Journal Experts is also acknowledged.

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Authors and Affiliations

  1. Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain

    Mireia Pérez-Verdaguer, Jesusa Capera, Joanna Bielanska, Núria Comes & Antonio Felipe

  2. Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain

    Mireia Pérez-Verdaguer, Jesusa Capera, Marta Camps & Antonio Felipe

  3. Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla, Av. Dr. Fedriani, s/n., 41009, Seville, Spain

    María Ortego-Domínguez & Rafael J. Montoro

  4. Max-Planck-Institute of Experimental Medicine, Molecular Biology of Neuronal Signals, AG Oncophysiology, Hermann-Rein-Str. 3, 37075, Göttingen, Germany

    Joanna Bielanska

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  1. Mireia Pérez-Verdaguer
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18_2018_2851_MOESM1_ESM.pdf

Supplementary Fig. 1. Kv1.5 did not target to lipid rafts. Lipid rafts were isolated from 3T3-L1 Wt and 3T3-L1 Cav 1− adipocytes. A sucrose gradient, from low (1)- to high (12)-density fractions was applied, and the expression of Kv1.5, clathrin (non-raft marker) and caveolin (lipid raft marker) was analyzed. (A) Expression of Kv1.5 in sucrose fractions from (A) 3T3-L1 wild type (WT) and (B) 3T3-L1 Cav 1− adipocytes. Kv1.5 distribution, out rafts, was independent of the expression of Cav 1. Note the limited augmentation of Cav 1 due to adipocyte differentiation in this cell line (PDF 124 kb)

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Pérez-Verdaguer, M., Capera, J., Ortego-Domínguez, M. et al. Caveolar targeting links Kv1.3 with the insulin-dependent adipocyte physiology. Cell. Mol. Life Sci. 75, 4059–4075 (2018). https://doi.org/10.1007/s00018-018-2851-7

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