Elevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patients

Abstract

Growth and differentiation factor 15 (GDF15) is a significant player in cellular stress and energy homeostasis. GDF15 is elevated in cancer cachexia, chemotherapy-induced anorexia, hyperemesis gravidarum, and mitochondrial disorders. Here we analyze GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by low weight and persistent restriction of food intake. While no significant difference in plasma GDF15 concentration was seen across the three included groups; active AN, recovered AN, and healthy controls, a subgroup of study participants with high GDF15 plasma was noted to a significantly higher extent in the AN groups. Sparse partial least squares discriminant analysis (sPLS-DA) identified six markers related to inflammatory processes or cellular stress from a set of 74 markers that distinguished AN with high GDF15 from the rest, with fibroblast growth factor 21 (FGF21) being the most important contributor. Moreover, FGF21 plasma concentration was significantly higher in the group with high GDF15, suggesting an involvement of mitochondrial dysfunction. In fact, mitochondrial polygenic risk score (PRS) was significantly associated with AN risk in a large AN case-control cohort. In line with this, we also report elevated liver expression of GDF15 in the anx/anx mouse displaying anorexia associated with mitochondrial dysfunction. We conclude that mitochondrial dysfunction should be further explored in AN. Clinical trials of GDF15 immunoneutralization in patients with AN and high levels of GDF15 are worthy of consideration.

Fig. 1. Growth and differentiation 15 (GDF15) concentration in plasma.

A Plasma GDF15 in anorexia nervosa (AN), recovered anorexia nervosa (AN-REC), and healthy controls (CTRL). The median is shown as a straight line and the box denotes the interquartile range. B Correlations between plasma GDF15 and body mass index (BMI) in AN (−0.32, p = 0.0084, 95% CI [−0.53, −0.079]), AN-REC (0.29, p = 0.0058, 95% CI [0.082, 0.48]), CTRL (−0.15, p = 0.21, 95% CI [−0.38, 0.09]), and all groups combined (−0.031, p = 0.64, 95% CI [−0.16, 0.10]). The colored lines correspond to the correlation for all groups, and for the AN, AN-REC, and CTRL groups separately. The shaded area around each linear fit line represents a 95% confidence interval (CI).

Fig. 2. Leptin concentration in plasma.

A Plasma leptin in anorexia nervosa (AN), recovered anorexia nervosa (ANREC), and healthy controls (CTRL). The median is shown as a straight line and the box denotes the interquartile range. B Correlations between plasma leptin and BMI in AN (0.28, p = 0.021, 95% CI [0.037, 0.49]), AN-REC (0.59, p = 1.94e–09, 95% CI [0.43, 0.71]), CTRL (0.55, p = 5.54e–07, 95% CI [0.36, 0.70]), and all groups combined (0.81, p 2.20e–16, 95% CI [0.75, 0.85]). C Correlations between plasma GDF15 and leptin in AN (−0.053, p = 0.67, 95% CI [−0.30, 0.20]), AN-REC (0.24, p = 0.028, 95% CI [0.020, 0.43]), CTRL (−0.16, p = 0.18, 95% CI [−0.39, 0.08]), and all groups combined (−0.013, p = 0.85, 95% CI [−0.15, 0.12]). The colored lines correspond to the correlation for all groups, and for the AN, AN-REC, and CTRL groups separately. The shaded area around each linear fit line represents a 95% confidence interval.

Fig. 3. Plasma immune markers.

A Sparse partial least squares discriminant analysis (sPLS-DA) sample plot of the 74 immune markers based on high GDF15 and normal GDF15 group with 95% confidence ellipses. Variances retained by the first two components are reported. B The loading plot represents the absolute values of the loading vectors for markers selected on Component 1 of the sPLS-DA model. C Volcano plot showing fold difference between high GDF15 group and normal GDF15 group. The x-axis represents fold change (log2), and the y-axis represents p-value (−log10). The data point representing FGF-21 is labeled (p = 0.0047). CDCP1 CUB domain-containing protein 1, CSF1 colony stimulating factor 1, FGF21 fibroblast growth factor 21, GDF15 growth and differentiation factor 15, HGF hepatocyte growth factor, TGF-a Transforming Growth Factor alpha.

Fig. 4

Odds Ratio (OR) with 95% confidence interval (95% CI) for anorexia nervosa (AN) by mitochondrial polygenic risk score (PRS) quartiles in ANGI-SE. The risk of AN is estimated using OR with 95% CI, with the lowest PRS quartile (1) as the reference group. The mitochondrial polygenic risk score (PRS) quartiles are defined as follows: 1 = low, 2 = mid-low, 3 = mid-high, and 4 = high.

Fig. 5. Liver expression of growth and differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) in anorectic mice.

A Relative expression levels of GDF15 and B FGF21 in anx/anx and wild-type female mice determined by qPCR. The bar charts present values as mean ± SD.