Endocrine Abstracts

Background: Fibroblast growth factor-21 (FGF21), which has recently been identified as a central regulator of metabolism, is known to be increased in conditions of obesity, insulin resistance, and fatty liver. Likewise, there is evidence that FGF21 increases with systemic inflammation. The aim of this study was to evaluate whether chronic low-grade inflammation might be the underlying mechanism and whether an anti-inflammatory treatment decreases FGF21 levels in metabolic disorders.

Methods: This is a secondary analysis of two interventional studies of treatment with an Interleukin-1 (IL-1)-receptor antagonist anakinra (Kineret®) in patients with obesity and features of the metabolic syndrome. The CortIL trial was a prospective interventional trial (n=61) investigating short-term effects of anakinra and dexamethasone in metabolic syndrome. The TestIL trial was a placebo controlled, double-blinded interventional trial (n=67) investigating longer-term effects of anakinra in metabolic syndrome versus placebo. FGF21 was measured at baseline, at day 2 and at 4 weeks of treatment with anakinra. Furthermore, FGF21 levels were measured after dexamethasone suppression test.

Results: Mean age of all includes patients (n=140) was 54 years (SD 12.1), 26% were female and the mean body mass index (BMI) was 37 kg/m2 (SD 4.8). Almost half of the patients were diabetic (45%) and had slightly increased c-reactive protein levels of 4.7 mg/L (SD 5.4), mirroring a state of chronic low-grade inflammation. FGF21 levels highly positively correlated with fasting glucose levels, HOMA-index, c-peptide levels, HbA1c and BMI. Treatment with anakinra led to a short-term reduction of FGF21 levels by 49.0 pg/mL (95% CI, (−205.9) – 107.9); P=0.064; however, this effect was no longer visible at 4 weeks (between-group difference: −8.8 pg/mL (95% CI, (−130.9) – 113.3); P=0.89. Short-term treatment with dexamethasone was associated with profound reduction of FGF21 by 174.5 pg/mL (95% CI, (−235.8) – (−113.2)); P<0.001.

Conclusions: Anti-inflammatory treatment led to a reduction of FGF21 levels in individuals with obesity and features of the metabolic syndrome. Chronic low-grade inflammation may be one of the key mediators for increased FGF21 in metabolic disorders.