Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals

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Background and purpose Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH. Methods Humans without ( n = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation. Results Serum GDF15 correlated negatively with M-value ( r = −0.35, p = 0.017) and NEFA suppression ( r = −0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence ( n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m 2 ) or absence of hepatic fibrosis ( n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m 2 ). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F P ; r = 0.35, p = 0.035) and maximal coupled (FNS P ; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN P in persons with fibrosis ( r = −0.48, p = 0.022). Conclusions In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.

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