Neuregulin 4 downregulation alters mitochondrial morphology and induces oxidative stress in 3T3-L1 adipocytes

Abstract

Neuregulin 4 (Nrg4) is an adipokine that belongs to the epidermal growth factor family andbinds to ErbB4 tyrosine kinase receptors. In 3T3-L1 adipocytes, the downregulation of Nrg4 expressionenhances inflammation and autophagy, resulting in insulin resistance. Here, we searched for thecauses of this phenotype. Nrg4 knockdown (Nrg4 KD) adipocytes showed a significant reduction inmitochondrial content and elongation, along with a lower content of the mitochondria fusion proteinmitofusin 2 (MFN2), and increased H2O2 production compared to the control scrambled cells (Scr).The antioxidant N-acetylcysteine reversed the oxidative stress and reduced the gene expression of thepro-inflammatory cytokine tumor necrosis factor α (TNFα). Nrg4 KD adipocytes showed enhancedlipolysis and reduced lipogenesis, in addition to a significant reduction in several intermediatesof the Krebs cycle. In summary, Nrg4 downregulation in adipocytes affects mitochondrial contentand functioning, causing impaired cellular metabolism, which in turn results in oxidative stress,inflammation, and insulin resistance.