Wagner Leonie, Estrada-Kunz Juliane, Roth Lisa, Weiner Juliane, Kralisch Susan, Hoffmann Annett, Stumvoll Michael, Fasshauer Mathias, Ebert Thomas, Krause Kerstin, Miehle Konstanze, Tönjes Anke
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig 04103, Germany.
Department of Nutritional Sciences, University of Giessen, Giessen 35390, Germany.
Endocrinology. 2025 Jul 8;166(9). doi: 10.1210/endocr/bqaf112.
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.
脂肪营养不良（LDs）是一种罕见的疾病，其特征是皮下脂肪组织部分或完全丧失，导致严重的代谢并发症。尽管米泊美生治疗已显示出有益效果，但其治疗效果有限，尤其是在部分LD患者中。神经调节蛋白4（NRG4）是棕色脂肪组织分泌的一种脂肪因子，可调节脂质代谢和肝功能，但其在LD中的相关性尚未得到研究。在本研究中，我们观察到与匹配的健康对照相比，LD患者的血清NRG4水平显著降低。在米泊美生治疗期间，NRG4水平进一步下降，这可能反映了脂肪量减少或治疗反应有限。为了探索功能相关性，我们用重组NRG4治疗转基因LD小鼠模型。虽然NRG4增强了棕色和腹股沟白色脂肪组织中的产热基因表达，但它并没有改善全身代谢参数或肝脂肪变性。在体外，NRG4未能挽救LD小鼠棕色脂肪细胞中受损的脂肪生成和产热，但增加了白色脂肪细胞中胰岛素刺激的脂肪酸摄取，这表明尽管存在分化缺陷，但功能反应仍然存在。NRG4还激活了肝脏中的AMPK信号通路，但没有改善脂质积累。这些发现表明，NRG4促进脂肪组织重塑，但不足以恢复LD中的全身代谢稳态。总之，我们的数据表明，NRG4的有益作用可能取决于功能性脂肪组织的存在，而在LD中这种组织严重受损。因此，虽然NRG4可能支持脂肪组织的局部可塑性，但作为LD中代谢恢复的疗法是不够的。
