The interplay of the adipokine neuregulin-4 on the inflammation, autophagy, oxidative stress and insulin responsiveness in adipocytes and skeletal muscle

Abstract

Neuregulin-4 has emerged as a novel adipokine in recent years. Several authors have previously explored the endocrine role of this adipocyte-secreted growth factor in the liver metabolism. In those studies, it has been shown that neuregulin-4 is a potent factor that protects against some of the deleterious effects induced by obesity and metabolic syndrome in the liver. However, the local role of this factor in adipocyte physiology remains unknown. Thus, in this study, we shed some light into the role of the adipose-tissue secreted neuregulin-4 in the physiology of adipocytes. To this end, we knocked down the expression of Nrg4 and its receptor, Erbb4, in 3T3-L1 adipocytes. Here, we show that the neuregulin-4/ErbB4 signalling axis disruption causes insulin resistance in adipocytes by promoting GLUT4 storage vesicle protein degradation through autophagy. In addition, neuregulin-4 and Erbb4-silenced adipocytes display cell-autonomous inflammation via NF-κB activation, which causes the down-regulation of the insulin receptor gene expression. Besides that, some studies have analysed the role of neuregulin-4 in the macrophage inflammation in inflammatory colitis. Inflammation drives insulin resistance and metabolic syndrome in pathologies such as type 2 diabetes. Therefore, we further explored the effects in the macrophage inflammation and polarization of the adipocyte-secreted neuregulin-4. To this end, we analysed the expression of proinflammatory and anti-inflammatory genes in bone marrow-derived and RAW 264.7 macrophages upon treatment with NRG4 derived from adipocytes. In this study, we show that macrophages treated with NRG4 from control adipocytes prevent and recover FROM the M1 polarization induced by lipopolysaccharide treatment. Besides the local effects of neuregulin-4 in the adipocyte and macrophage physiology, the distal effects of these adipokines in the skeletal muscle physiology are yet to be explored. Previous studies have described that neuregulin-1 promotes oxidative metabolism and mitochondrial biogenesis in skeletal muscle. Therefore, we analysed the role of the adipokine neuregulin-4 in skeletal muscle physiology and whether this has consequences on the crosstalk of muscle with other metabolic tissues. Hence, we analysed the phenotype of muscle-specific Erbb4 gene-deleted mice at 2 and 6 months. Here, we show that the absence of neuregulin-4 action in skeletal muscle triggers inflammation in this tissue. Furthermore, the hepatic expression of neuregulin-4 is indirectly ablated in these mice. Upon high-fat diet feeding, 6-months-old muscle-specific Erbb4 gene-deleted mice display less triacylglyceride accumulation in skeletal muscle and diminished the white adipose tissue mass, which is consistent with the emergence of systemic inflammation upon Erbb4 gene deletion in skeletal muscle. In all, in this study, we highlight the importance of the novel adipokine neuregulin-4 as an anti-inflammatory factor with local and systemic effects that contribute to the preservation of insulin sensitivity in the organism.