Neuregulin 4 Downregulation Alters Mitochondrial Morphology and Induces Oxidative Stress in 3T3-L1 Adipocytes
Neuregulin 4 (Nrg4) is an adipokine that belongs to the epidermal growth factor family and binds to ErbB4 tyrosine kinase receptors. In 3T3-L1 adipocytes, the downregulation of <i>Nrg4</i> expression enhances inflammation and autophagy, resulting in insulin resistance. Here, we searched for the causes of this phenotype. Nrg4 knockdown (Nrg4 KD) adipocytes showed a significant reduction in mitochondrial content and elongation, along with a lower content of the mitochondria fusion protein mitofusin 2 (MFN2), and increased H<sub>2</sub>O<sub>2</sub> production compared to the control scrambled cells (Scr). The antioxidant N-acetylcysteine reversed the oxidative stress and reduced the gene expression of the pro-inflammatory cytokine tumor necrosis factor α (TNFα). Nrg4 KD adipocytes showed enhanced lipolysis and reduced lipogenesis, in addition to a significant reduction in several intermediates of the Krebs cycle. In summary, Nrg4 downregulation in adipocytes affects mitochondrial content and functioning, causing impaired cellular metabolism, which in turn results in oxidative stress, inflammation, and insulin resistance.
Authors
- Sı́lvia Busquets (ORCID: https://orcid.org/0000-0002-9319-3555)
- Julián Aragonés (ORCID: https://orcid.org/0000-0002-0193-4679)
- Wifredo Ricart (ORCID: https://orcid.org/0000-0002-3452-9098)
- Iliana López‐Soldado (ORCID: https://orcid.org/0000-0001-5890-6073)
- David Sebastián (ORCID: https://orcid.org/0000-0002-7260-3869)
- Montserrat Romero (ORCID: https://orcid.org/0000-0002-2801-6376)
- Xavier Testar (ORCID: https://orcid.org/0000-0002-8330-8873)
- Cristina Balcells (ORCID: https://orcid.org/0000-0002-7927-5538)
- António Zorzano (ORCID: https://orcid.org/0000-0002-1638-0306)
- Francisco J. López‐Soriano (ORCID: https://orcid.org/0000-0003-1493-3023)
- Marta Camps (ORCID: https://orcid.org/0000-0001-5392-1792)
- José María Moreno‐Navarrete (ORCID: https://orcid.org/0000-0002-2883-511X)
- Anna Gumà (ORCID: https://orcid.org/0000-0001-9390-5252)
- Francisco Díaz‐Sáez (ORCID: https://orcid.org/0000-0002-5881-1928)
- José Manuel Fernández‐Real (ORCID: https://orcid.org/0000-0002-7442-9323)
- Marta Cascante (ORCID: https://orcid.org/0000-0002-2062-4633)
- Laura Rosselló
Institutions
- Universitat de Girona (ES)
- Instituto de Salud Carlos III (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Hospital Universitario Santa Cristina (ES)
- Institut d'Investigació Biomèdica de Girona (ES)
- Centro de Investigación Biomédica en Red (ES)
- Institute for Research in Biomedicine (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Institut de Biomedicina de la Universitat de Barcelona
- Universidad Autónoma de Madrid (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2024-10-31
- DOI
- https://doi.org/10.3390/ijms252111718
- Citations
- 5
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Fundación Ramón Areces
- Fundació la Marató de TV3
- Ministerio de Ciencia, Innovación y Universidades
- Centres de Recerca de Catalunya
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas
- Instituto de Salud Carlos III