BACKGROUND Fibronectin type III domain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. METHODS Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. RESULTS Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. CONCLUSIONS Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.

中文翻译：

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FNDC4，一种新型脂肪因子，可减少脂肪生成并促进人内脏脂肪细胞的脂肪褐变。

背景技术含有纤连蛋白III型结构域的蛋白4（FNDC4）构成了分泌因子，其在纤连蛋白III型和跨膜结构域中与运动相关的肌动蛋白鸢尾素（FNDC5）具有高度同源性。我们试图评估FNDC4是否模仿人脂肪组织中FNDC5 / irisin的抗肥胖作用。方法本研究采用78例肥胖病患者的减肥手术和26例体重正常的个体的血浆和脂肪组织样本。结果：病态肥胖患者的血浆FNDC4减少，与肥胖相关的全身炎症有关，并且在减肥手术后六个月保持不变。病态肥胖患者的内脏脂肪组织无论胰岛素抵抗程度如何，均显示较高的FNDC4及其假定受体GPR116的表达。FNDC4的含量受人内脏脂肪细胞中的脂肪生成，脂肪分解和促炎性刺激的调节。FNDC4减少了人类脂肪细胞中的胞内脂质积聚并刺激了褐色样模式，这由UCP-1和褐色/米色脂肪细胞标志物PRDM16，TMEM26和CD137的表达上调所证明。此外，FNDC4处理上调线粒体DNA含量和线粒体生物发生相关因子（TFAM，NRF1和NRF2）。人FNDC4组合式脂肪细胞表现出脂肪生成的增加和褐色/米色特定脂肪标记物的减少，以及线粒体生物发生中涉及的因素。结论综合起来，新型脂肪因子FNDC4减少人内脏脂肪细胞的脂肪生成并增加脂肪褐变。人内脏脂肪中FNDC4的上调可能构成了减轻肥胖状态下脂肪细胞肥大，炎症和米色脂肪形成受损的尝试。