GDF15 linked to maternal risk of nausea and vomiting during pregnancy

Abstract

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1–4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

The Energetic Stress Marker GDF15 is Induced by Acute Psychosocial Stress

“…Curiously, both participants exhibited abnormally high GDF15 levels throughout the protocol -the highest average GDF15 observed across our control cohorts (see Figure S4G-I). Given that high GDF15 levels signaling on the brainstem causes aversive responses and visceral malaise (e.g., nausea 4,63 ), we speculate that their decision not to return for the second visit could have been influenced by the particularly aversive experience of their first visit, possibly either enhanced or provoked by abnormally high plasma GDF15 levels. Third, the saliva GDF15 awakening response, measured across three days, was highest on the first day (Monday) and progressively declined as the psychological novelty of the daily exercise subsided.…”

“…Participants interested in the study underwent a multi-stage screening process. Inclusion criteria included being 20-49 years of age at the time of screening, having a body mass index between 20-34.9 kg/m 2 , healthy habitual sleep patterns, and habitually consuming the first meal of the day within 1 h of waking. Individuals who were pregnant or lactating, smoked (currently or <3 years since stopping), reported excessive caffeine or alcohol intake, had extreme morning or evening chronotype, or who were actively engaging in intentional weight change or had a recent weight change >5% in the past 3 months were excluded.…”

“…The circulating metabokine-cytokine growth differentiation factor 15 (GDF15) is among the most studied circulating proteins in biomedicine. Circulating GDF15 is produced by various somatic tissues and cell types, secreted and transported in the blood, eventually reaching the hindbrain (and possibly other tissues) where it signals energetic stress to alter behavior and whole-body energy expenditure [1][2][3][4][5] . GDF15 fulfills several criteria as a marker of systemic energetic stress: 1) GDF15 is the most robustly elevated circulating protein with aging 6,7 , 2) it is induced by some medications targeting mitochondria (e.g., metformin 8 ), and 3) it is elevated in several chronic physical and mental illnesses including cardiovascular disease 9 , cancer 10 , mood disorders 11 , Alzheimer's disease 12,13 autoimmune diseases 14 , and others.…”

“…GDF15 is also secreted in response to various non-disease states. Blood GDF15 increases with nutritional and physiological stressors such as exhaustive exercise 27,28 , pregnancy 2,29 , starvation 30 , and infectious challenges 31 . This secretion pattern aligns with the canonical, energy-mobilizing glucocorticoid and sympathetic hormonal pathways, with which GDF15 interacts 1,5,32 , and may contribute to GDF15-mediated increase in energy expenditure 1,33 .…”

Identification and characterization of human GDF15 knockouts

“…In the PGR, we identified a total of 13 LOF variants comprising protein truncating nonsense and frameshift substitutions in GDF15 , with a cumulative allele frequency of 0.027% (Extended Data Table 1) that includes one predicted KO. Additionally, a review of missense variants that may impact function revealed a variant, Cys211Gly (C211G), in a position that is highly conserved across species and across GDNF family members (Figure 1A) and has been recently suggested to be LOF 3 . In PGR, we identified 123 heterozygous carriers and 4 homozygous carriers of C211G (Extended Data Table 1), with an allele frequency of 0.086%.…”