Growth differentiation factor 15 (GDF15) is associated with non-alcoholic fatty liver disease (NAFLD) in youth with overweight or obesity

Abstract

Objective Growth differentiation factor 15 (GDF15) has been associated with food intake and weight regulation in response to metabolic stress. In animal models, it has been noted that it may play a role in the progression of non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Design In the current study, we explored the association of circulating plasma concentrations of GDF15 with NAFLD in youth with overweight/obesity, and whether changes in plasma concentrations in GDF15 parallel the changes in intrahepatic fat content (HFF%) over time. Methods Plasma GDF15 concentrations were measured by ELISA in 175 youth with overweight/obesity who underwent an oral glucose tolerance test (OGTT) and magnetic resonance imaging (MRI) to assess intrahepatic, visceral, and subcutaneous fat. Baseline fasting GDF15 concentrations were measured in twenty-two overweight/obese youth who progressed (n = 11) or regressed (n = 11) in HFF% by more than 30% of original over a 2-year period. Results Youth with NAFLD had significantly higher plasma concentrations of GDF15 than those without NAFLD, independent of age, sex, ethnicity, BMI z-score (BMIz), and visceral fat (P = 0.002). During the OGTT, there was a decline in plasma GDF15 concentrations from 0 to 60 min, but GDF15 concentrations returned to basal levels by the end of the study. There was a statistically significant association between change in HFF% and change in GDF15 (P = 0.008; r2 = 0.288) over ~2 years of follow-up. Conclusions These data suggest that plasma GDF15 concentrations change with change in intrahepatic fat content in youth with overweight/obesity and may serve as a biomarker for NAFLD in children.

Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice

“…We [ 33 ] and others [ [34] , [35] , [36] ] have shown that activation of the ISR (via nutritional, genetic or pharmacological stressors) is associated with increased expression of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21). Plasma levels of both FGF21 [ [37] , [38] , [39] , [40] , [41] ] and GDF15 [ [42] , [43] , [44] ] are known to be increased in obese humans and rodents as well as in other metabolic disease states such as insulin resistance [ 45 , 46 ], NAFLD [ [47] , [48] , [49] , [50] , [51] , [52] ] and mitochondrial disease [ 53 , 54 ]. Both stress-induced cytokines, GDF15 and FGF21, have attracted considerable interest as potential therapies for obesity and its associated metabolic disease [ 55 ].…”

Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice

“…We (Patel et al, 2019) and others (Chung et al, 2017; Dong et al, 2015; Laeger et al, 2014) have shown that activation of the ISR (via nutritional, genetic or pharmacological stressors) is associated with increased expression of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21). Plasma levels of both FGF21 (Gómez-Ambrosi et al, 2017; Kharitonenkov et al, 2005; Kralisch et al, 2013; Reinehr et al, 2012; Zhang et al, 2008) and GDF15 (Carballo-Casla et al, 2021; Vila et al, 2011; Xiong et al, 2017) are known to be increased in obese humans and rodents as well as in other metabolic disease states such as insulin resistance (Chavez et al, 2009; Kempf et al, 2012), NAFLD (Bilson et al, 2021; Dushay et al, 2010; Galuppo et al, 2022; Kim et al, 2018; Rusli et al, 2016; Tucker et al, 2019) and mitochondrial disease (Poulsen et al, 2020; Suomalainen et al, 2011). Both stress-induced cytokines, GDF15 and FGF21, have attracted considerable interest as potential therapies for obesity and its associated metabolic disease (Keipert and Ost, 2021).…”

Heart failure with preserved ejection fraction and non‐alcoholic fatty liver disease: new insights from bioinformatics

“…A meta‐analysis of 51 studies involving 36 074 patients and 47 052 controls showed that elevated levels of CRP, IL‐1β, IL‐6, TNF‐α, and intercellular cell adhesion molecule‐1 were significantly associated with increased risk of NAFLD 49 . Plasma GDF15 concentration was measured in 175 overweight/obese adolescents and showed that GDF15 changed with changes in intrahepatic fat content 50 . Ectodysplasin A, a liver secreted protein, is elevated in NAFL and NASH and is associated with progression of steatosis and fibrosis 51 .…”

“…49 Plasma GDF15 concentration was measured in 175 overweight/obese adolescents and showed that GDF15 changed with changes in intrahepatic fat content. 50 Ectodysplasin A, a liver secreted protein, is elevated in NAFL and NASH and is associated with progression of steatosis and fibrosis. 51 Moreover, a Korean study involving 2735 participants showed an inverse association between adiponectin and the prevalence of NAFLD and could even serve as a novel biomarker for NAFLD.…”