GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement

Melvin A,Chantzichristos D,Walker Br,Kyle Cj,Stimson Rh,Johannsson G,ORahilly S,Mackenzie Sd

doi:10.1530/ey.17.8.16

Abstract

CONTEXT GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. OBJECTIVE To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. METHODS AND RESULTS We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. CONCLUSIONS GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.

Highlights

GDF15 was first identified in 1997 as a novel transcript from a macrophage cell line and classified as a member of the TGF superfamily (1)
Aligned with the view that GDF15 represents a marker of cellular stress, increased expression u and secretion of GDF15 has been demonstrated when the cellular integrated stress response (ISR) n pathway is activated (4, 5, 6) suggesting that GDF15 represents an endocrine arm of the cellular ISR. a Key advances in the understanding of the functional biology of GDF15 have come from the M observations that a) overexpression of GDF15 in mice resulted in weight loss and reduced energy d intake (7); b) GDF15 knockout mice have increased body mass and energy intake compared to wildte type counterparts (8); and c) GDF15 seemingly mediates these effects on energy intake and body p mass through the hind brain (9)
Similar associations have been observed in cardiac failure where higher GDF15 serves as a biomarker for mortality risk but there is an inverse relationship seen between GDF15 and body mass index (BMI) (17)

Summary

Introduction

GDF15 ( called MIC-1) was first identified in 1997 as a novel transcript from a macrophage cell line and classified as a member of the TGF superfamily (1). Citation for published version: Melvin, A, Chantzichristos, D, Kyle, CJ, Mackenzie, SD, Walker, BR, Johannsson, G, Stimson, RH & O’rahilly, S 2019, 'GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement', Journal of Clinical Endocrinology & Metabolism.

Results

Conclusion