Patt Marie, Karkossa Isabel, Krieg Laura, Massier Lucas, Makki Kassem, Tabei Shirin, Karlas Thomas, Dietrich Arne, Gericke Martin, Stumvoll Michael, Blüher Matthias, von Bergen Martin, Schubert Kristin, Kovacs Peter, Chakaroun Rima M
University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany.
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany.
EBioMedicine. 2024 Dec;110:105458. doi: 10.1016/j.ebiom.2024.105458. Epub 2024 Nov 27.
This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery.
We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes.
FGF21 levels were linked to central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, and were driven by circulating leptin and liver enzymes. Higher FGF21 were linked with AT dysfunction reflected in fibro-inflammatory and lipid dysmetabolism pathways. Specifically, visceral AT inflammation was tied to both FGF21 elevation and liver dysfunction. Post-surgery, FGF21 peaked transitorily at three months. Mediation analysis highlighted an underlying increased AT catabolic state with elevated free fatty acids (FFA), contributing to higher liver stress and FGF21 levels (total effect of free fatty acids on FGF21 levels: 0.38, p < 0.01; proportion mediation via liver 32%, p < 0.01). In line with this, histological AT fibrosis linked with less pronounced FGF21 responses and reduced fat loss post-surgery (FFA and visceral AT fibrosis: rho = -0.31, p = 0.030; FFA and fat-mass loss: rho = 0.17, p = 0.020).
FGF21 reflects the liver's disproportionate metabolic stress response in both central adiposity and after metabolic surgery, with its dynamics reflecting an AT-liver crosstalk.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838, CRC1382 and a Walther-Benjamin Fellowship and by a junior research grant by the Medical Faculty, University of Leipzig, and by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501. Part of this work was supported by the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 and by the CRC1382 and the Novo Nordisk Foundation and by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project number 530364326.
本研究调查了一个反映代谢疾病进展的队列中循环成纤维细胞生长因子21（FGF21）水平的决定因素，研究循环FGF21与脂肪组织（AT）形态和功能以及代谢手术后代谢调整之间的关联。
我们对678名个体进行了横断面血清FGF21测量，并对189名接受代谢手术的个体进行了纵向测量。使用单变量和多变量分析、因果中介分析以及AT转录组和蛋白质组的网络整合，评估FGF21水平、AT组织学、转录组和蛋白质组、心脏代谢危险因素以及手术后代谢调整之间的关系。
FGF21水平与中心性肥胖、亚临床炎症、胰岛素抵抗和心脏代谢风险相关，并受循环瘦素和肝酶驱动。较高的FGF21与纤维炎症和脂质代谢紊乱途径中反映的AT功能障碍有关。具体而言，内脏AT炎症与FGF21升高和肝功能障碍均有关联。手术后，FGF21在三个月时短暂达到峰值。中介分析突出了潜在的AT分解代谢状态增加，游离脂肪酸（FFA）升高，导致肝脏压力增加和FGF21水平升高（游离脂肪酸对FGF21水平的总效应：0.38，p<0.01；通过肝脏的中介比例32%，p<0.01）。与此一致，组织学上的AT纤维化与不太明显的FGF21反应以及手术后脂肪减少有关（FFA与内脏AT纤维化：rho=-0.31，p=0.030；FFA与脂肪量减少：rho=0.17，p=0.020）。
FGF21反映了在中心性肥胖和代谢手术后肝脏不成比例的代谢应激反应，其动态变化反映了AT-肝脏的相互作用。
这项工作得到了德国研究基金会（DFG）通过CRC 1052（项目编号209933838）、CRC1382以及沃尔特·本杰明奖学金的支持，还得到了莱比锡大学医学院的初级研究资助以及德国联邦教育与研究部（BMBF）的资助，项目编号：01EO1501。这项工作的一部分得到了欧盟第七框架研究、技术开发和示范计划的资助，资助协议编号为HEALTH-F4-2012-305312，以及CRC1382、诺和诺德基金会和德国研究基金会（DFG）项目编号530364326的支持。
