The Impact of Neuregulin 4 on Metabolic Dysregulation in Lipodystrophy.

Lipodystrophies (LDs) are rare disorders characterized by the partial or complete loss of subcutaneous adipose tissue, leading to severe metabolic complications. Although metreleptin therapy has shown beneficial effects, its therapeutic efficacy is limited, particularly in patients with partial LD. Neuregulin 4 (NRG4), a batokine secreted by brown adipose tissue, regulates lipid metabolism and hepatic function, but its relevance in LD has not been investigated. In this study, we observed significantly reduced serum NRG4 levels in patients with LD compared to matched healthy controls. NRG4 levels declined further during metreleptin therapy, potentially reflecting fat mass reduction or limited treatment response. To explore functional relevance, we treated a transgenic LD mouse model with recombinant NRG4. While NRG4 enhanced thermogenic gene expression in brown and inguinal white adipose tissue, it did not improve systemic metabolic parameters or hepatic steatosis. In vitro, NRG4 failed to rescue impaired adipogenesis and thermogenesis in brown adipocytes from LD mice but increased insulin-stimulated fatty acid uptake in white adipocytes, indicating a preserved functional response despite differentiation defects. NRG4 also activated hepatic AMPK signaling without improving lipid accumulation. These findings suggest that NRG4 promotes adipose tissue remodeling but is insufficient to restore systemic metabolic homeostasis in LD. Together, our data indicate that NRG4's beneficial effects may depend on the presence of functional adipose tissue, which is profoundly impaired in LD. Consequently, while NRG4 may support local plasticity in adipose tissue, it is insufficient as a therapy for metabolic restoration in LD.