FGF21 reflects a responsive adipose tissue-liver axis in both cardiometabolic burden and following metabolic surgery

Objective This research aims to uncover the factors associated with circulating FGF21 levels in a cohort mimicking metabolic disease progression, examining its relationship with adipose tissue (AT) morphology and function. It also investigates FGF21 level changes post-metabolic surgery, predictive factors, and their links to metabolic adjustments. Design In this observational study, serum FGF21 was measured in 678 individuals cross-sectionally and longitudinally in 189 undergoing metabolic surgery. We explored links between FGF21, AT histology, cardiometabolic risk factors, weight loss, glucose metabolism changes using feature selection algorithms, univariate/multivariate models, and transcriptome/proteome network analyses in subcutaneous and visceral AT. Results FGF21 levels track closely with central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, with circulating leptin emerging as the top predictor. Visceral AT inflammation was associated with liver dysfunction and FGF21 elevation. Post-surgery, FGF21 peaked transitorily at 3 months and predicted fat mass loss at 12 months but not HOMA-IR improvements. Mediation analysis indicated an increased catabolic and AT-lipolytic state associated with higher liver enzyme and FGF21 levels (total effect 0.38, p<0.01; proportion mediation 32%, p<0.01). AT fibrosis was related to a blunted transitory FGF21 increase, and lower fat loss, and hence linked with a reduced surgical effect (FFA and visceral AT fibrosis: rho=-0.31, p=0.030; FFA and fat-mass loss: rho=0.17, p=0.020). Conclusion FGF21 reflects the liver’s metabolic response to AT characteristics in both central adiposity and after metabolic surgery, with its dynamics reflecting AT-liver crosstalk.