ArticleInternational journal of molecular sciences2021
Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.
- The impact of serum neuregulin 4 (NRG-4) levels on non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis.BMC gastroenterology · 2025Pooled it
- Expression and significance of ependymin-related protein 1 and neuregulin 4 in the serum of patients with polycystic ovary syndrome.International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics · 2026Article
- Neuregulin 4 in Insulin Resistance: Mechanisms, Controversies, and Therapeutic Perspectives.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Review
- The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment.Journal of the American College of Cardiology · 2025Review
- Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.Diabetologia · 2025Article
- Levels of DEFA1, Progranulin, and NRG4 in Patients with Autonomic Neuropathy: Potential Biomarkers for Diagnosis and Prognosis.Metabolites · 2025Article
- Adipose tissue dysfunction disrupts metabolic homeostasis: mechanisms linking fat dysregulation to disease.Frontiers in endocrinology · 2025Review
- Novel secreted regulators of glucose and lipid metabolism in the development of metabolic diseases.Diabetologia · 2024Review
- Neuregulin 4 Downregulation Alters Mitochondrial Morphology and Induces Oxidative Stress in 3T3-L1 Adipocytes.International journal of molecular sciences · 2024Article
- Neuregulin-4 protects cardiomyocytes against high-glucose-induced ferroptosis via the AMPK/NRF2 signalling pathway.Biology direct · 2024Article
- The journey towards physiology and pathology: Tracing the path of neuregulin 4.Genes & diseases · 2024Review
- The Potential of Neuregulin 4 as a Novel Biomarker and Therapeutic Agent for Vascular Complications in Type 2 Diabetes Mellitus.Journal of inflammation research · 2024Review
- Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis.Frontiers in endocrinology · 2024Review
- Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway.Cardiovascular diabetology · 2022Article
- Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells.Frontiers in physiology · 2022Article
- Neuregulin 4 as a novel adipokine in energy metabolism.Frontiers in physiology · 2022Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy.
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