ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2020; 105(5): 1427–1434. PMID: 31853550.

GDF15 is a stress-induced hormone that acts in the hindbrain to activate neural circuits involved in aversive responses and reducing food intake and body weight in animal models (1). In humans, GDF15 is widely expressed, with highest concentrations seen in placental trophoblasts, followed by kidney, bladder, prostate, gastrointestinal, pancreatic, lung, liver, and adipose tissue (2). GDF15 expression is increased when the cellular integrated stress response (ISR) pathway is activated, suggesting that GDF15 represents an endocrine arm of the cellular ISR (3). Interestingly, GDF15 has been reported to have a diurnal rhythm with a peak at ˜0000 h and nadir at ~1200 h, but it is unknown whether this is entrained by the normal circadian rhythm of cortisol secretion (4).

This randomized cross-over, single-blind trial of subjects with Addison’s disease tested whether circulating GDF15 concentrations are regulated by glucocorticoids and may contribute to the nausea, vomiting or anorexia symptoms frequently observed in adrenal insufficiency. GDF15 concentrations were elevated in untreated patients with primary adrenal insufficiency compared with matched healthy controls, and glucocorticoid replacement reduced these differences in a dose-dependent manner.

This study shows that GDF15 concentrations are negatively regulated by glucocorticoids. Further studies are needed on the causal relationships between glucocorticoids and GDF15 concentrations on symptoms of nausea, vomiting, anorexia, and weight loss in adrenal insufficiency, and also the typical increased appetite and weight gain in states of glucocorticoid excess.

References:

1. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGFsuperfamily. Proceedings of the National Academy of Sciences. 1997; 94(21):11514–11519.

2. Tsai VW, Macia L, Johnen H, et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS ONE. 2013;8(2): e55174.

3. Patel S, Alvarez-Guaita A, Melvin A, et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 2019; 29(3):707–718.e8.

4. Tsai VW, Macia L, Feinle-Bisset C, et al. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLoS ONE. 2015;10(7):e0133362.