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Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways

  • Signaling and Cell Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences insulin sensitivity in vivo, and the underlying signaling pathways have been scarcely studied. We studied how a progressive reduction in UCP3 expression (using UCP3 +/+, UCP3 +/−, and UCP3 −/− mice) modulates insulin sensitivity and related metabolic parameters. In order to further validate our observations, we also studied animals in which insulin resistance was induced by administration of a high-fat diet (HFD). In UCP3 +/− and UCP3 −/− mice, gastrocnemius muscle Akt/protein kinase B (Akt/PKB) (serine 473) and AMP-activated protein kinase (AMPK) (threonine 171) phosphorylation, and glucose transporter 4 (GLUT4) membrane levels were reduced compared to UCP3 +/+ mice. The HOMA-IR index (insulin resistance parameter) was increased both in the UCP3 +/− and UCP3 −/− mice. In these mice, insulin administration normalized Akt/PKB phosphorylation between genotypes while AMPK phosphorylation was further reduced, and sarcolemmal GLUT4 levels were induced but did not reach control levels. Furthermore, non-insulin-stimulated muscle fatty acid oxidation and the expression of several involved genes both in muscle and in liver were reduced. HFD administration induced insulin resistance in UCP3 +/+ mice and the aforementioned parameters resulted similar to those of chow-fed UCP3 +/− and UCP3 −/− mice. In conclusion, high-fat-diet-induced insulin resistance in wild-type mice mimics that of chow-fed UCP3 +/− and UCP3 −/− mice showing that progressive reduction of UCP3 levels results in insulin resistance. This is accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and AMPK signaling.

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Acknowledgment

This study was supported by a Grant from Ministero dell’Istruzione dell’Università, e della Ricerca COFIN—Protocol Number 20089SRS2X.

Ethical standards

The experiments comply with the current Italian laws.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100, Caserta, Italy

    Rosalba Senese, Vivien Valli, Federica Cioffi, Antonia Lanni & Pieter de Lange

  2. Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port’Arsa 11, 82100, Benevento, Italy

    Maria Moreno, Elena Silvestri & Fernando Goglia

  3. Dipartimento delle Scienze Biologiche, Sez. Fisiologia ed Igiene, Università degli Studi di Napoli “Federico II”, Via Mezzocannone 8, 80134, Naples, Italy

    Assunta Lombardi & Rosa Anna Busiello

Authors
  1. Rosalba Senese
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  2. Vivien Valli
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  3. Maria Moreno
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  4. Assunta Lombardi
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  6. Federica Cioffi
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  7. Elena Silvestri
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  8. Fernando Goglia
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  9. Antonia Lanni
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  10. Pieter de Lange
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Corresponding authors

Correspondence to Antonia Lanni or Pieter de Lange.

Additional information

Rosalba Senese and Vivien Valli contributed equally to the work.

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Senese, R., Valli, V., Moreno, M. et al. Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways. Pflugers Arch - Eur J Physiol 461, 153–164 (2011). https://doi.org/10.1007/s00424-010-0892-3

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  • DOI: https://doi.org/10.1007/s00424-010-0892-3

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