GDF15 linked to maternal risk of nausea and vomiting during pregnancy 2023 Fejzo et al (hyperemesis gravidarum - morning sickness in pregnancy)

[Andy]

Extreme morning sickness? Scientists finally pinpoint a possible cause

"Researchers have pinpointed a hormone released by growing fetuses that might cause a debilitating form of morning sickness. Women who are more sensitive to the hormone, which increases during early pregnancy, might be at greater risk of experiencing a severe form of nausea and vomiting, called hyperemesis gravidarum, according to their study.

“For the first time, hyperemesis gravidarum could be addressed at the root cause, rather than merely alleviating its symptoms,” says Tito Borner, a physiologist at the University of Pennsylvania. The work was published on 13 December in Nature1.

The finding could also open avenues for treatment. “We now have a clear view of what may cause this problem and a route for both treatment and prevention,” says study co-author Stephen O’Rahilly, a metabolism researcher at the University of Cambridge, UK."

https://www.nature.com/articles/d41586-023-03982-8

 

[Andy]

Of possible interest is this study, Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2019, Melvin, Lacerda, Nacul et al

 

[Amw66]

Metformin being postulated as a potential treatment on radio today.

 

[SNT Gatchaman]

See also recent review Intracellular to Interorgan Mitochondrial Communication in Striated Muscle in Health and Disease (2023, Endocrine Reviews), authors including Rob Wüst —

• Myomitokines, such as FGF21, GDF15, and mtDNA, can alter whole-body physiology and systemic responses

In the last decade, it has become clear that mitochondria are not solely on the receiving end of substrate oxidation, but that mitochondria actively communicate with other mitochondria as well as other organelles, such as the nucleus, lipid droplets, peroxisomes, and endo-/sarcoplasmic reticulum.

Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor β (TGF-β) superfamily with pleiotropic functions

Upon activation of the integrated stress response, CHOP and ATF4 regulate the transcription of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two metabolic hormones with autocrine, paracrine, and endocrine actions. Muscle-derived FGF21 and GDF15 are systemic mediators of the integrated stress response

 

[Andy]

Thought this also seemed interesting,
GDF15 promotes weight loss by enhancing energy expenditure in muscle, 2023, Wang et al

Abstract
Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4,5,6,7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL–β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

 

[SNT Gatchaman]

It's also worth noting that this finding was foreshadowed by an earlier GWAS study via 23andMe —

Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum (2018)
Fejzo, Marlena S.; Sazonova, Olga V.; Sathirapongsasuti, J. Fah; Hallgrímsdóttir, Ingileif B.; Vacic, Vladimir; MacGibbon, Kimber W.; Schoenberg, Frederic P.; Mancuso, Nicholas; Slamon, Dennis J.; Mullin, Patrick M.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10−8 ) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.

Link | PDF (Nature Communications)

They concluded —

Future research should focus on functional follow-up. Since GDF15 and IGFBP7 levels are upregulated during placentation and cachexia, and downregulated prior to miscarriage, serum concentrations of GDF15 and IGFBP7 should now be studied in pregnant women with and without HG.

 

[Deanne NZ]

I just listened to the author interviewed on Radio NZ today and immediately came here to check if her findings had been discussed. My thought was that could this be relevant to those with severe MECFS who experience extreme nausea & vomiting. It is fascinating.

 

[SNT Gatchaman]

https://www.rnz.co.nz/national/prog...-morning-sickness-so-she-discovered-the-cause

 

[Hutan]

Yes, I thought it was a good interview. Worth a listen. (Seems like a fair chunk of S4ME's NZ members listen to RadioNZ.)

Metformin being postulated as a potential treatment on radio today.

It was interesting to hear that Marlena Fejzo is trialling metformin.

I've merged this thread with an earlier thread on the same topic.

The interview covers the same ground as the article at the beginning of the thread in terms of the sexism and gaslighting Marlena experienced, including being accused of seeking the 'secondary benefit' of attention from her parents, when she was vomiting so constantly that she was starving and lost her baby.

 

[SNT Gatchaman]

This is a 20 minute listen and the backstory is highly relevant to the historical and current ME/CFS research situation. Following her discovery (against the wind and tide of grant reviewers and medical misogyny) she now hopes for treatment trials. One of those is using metformin to increase GDF15 levels prior to pregnancy to de-sensitise Mum prior to the fetus producing it.

(Edit: sync-post with Hutan)

 

[Hutan]

Of possible interest is this study, Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2019, Melvin, Lacerda, Nacul et al

The connection with severe ME/CFS, and particularly those who experience difficulties eating are certainly interesting.

Off the top of my head:
It seems the women who experience hyperemesis gravidarum are reacting to the GDF15 that is produced by the pregnancy. And the idea is that the metformin given to women with the gene that predisposes to this sensitivity prior to a pregnancy increases GDF15, in order to desensitise. So, metformin increases GDF15.

And it's been found that GDF15 levels are slightly elevated in people with mild ME/CFS, and significantly elevated in people with severe ME/CFS.

And there are suggestions that metformin might help people with ME/CFS, and that, when taken during acute Covid-19, it might decrease the risk of Long Covid. So, increasing GDF15 levels helps, even when GDF15 seems to be associated with worse ME/CFS???

Have I got those things right, and are there any other bits of the puzzle that make things hang together better?

It would be great to have Marlena Fejzo visit the forum.

 

[Hutan]

Reading about GDF15:
GDF15: a potential therapeutic target for type 1 diabetes

Multiple studies have now shown that GDF15 plays a critical anti-inflammatory role in tissue injury. Most of our mechanistic insights on the role of GDF15 in inflammation come from an early study by Kempf and colleagues, who reported that GDF15 inhibits integrin activation and thereby dampens cytokine signaling and infiltration of pro- inflammatory cells in heart infarcts [35]. In addition, Abulizi et al. and Santos et al. demonstrated that GDF15 deficiency exacerbates the inflammatory response to the sepsis affected tissue, but its role is highly contextual [36,37]. Similarly, in animal models of T1D, Deelman and colleagues showed that GDF15 deficiency results in increased expression of inflammatory markers [38].

Levels of GDF15 are impacted by plethora of metabolic factors, exercise, tissue injury, pregnancy, hypoxia, and drugs like metformin and rapamycin represented in Fig. 2.

Often increased circulating GDF15 levels documented in various disease pathologies are contradictory, yet the exogenous administration of GDF15 has consistently been demonstrated to be beneficial in regulating normal cellular functions [95-99].

High GDF15 levels induce vomiting and nausea in patients, posing a critical risk to GDF15 therapeutic endeavors [104,105]. As a result, exploring small molecules like XIB4035 and BT13, which can mimic GDF15 effects by targeting GFRAL/RET receptor signaling, could potentially increase the target specificity and reduce off-target effects [34,106].

The study accounted for various SNPs found in serum GDF15; however, there is a possibility of GDF15 existing in 4 different protein forms in the serum, out of which only one is considered active and thought to produce the characteristic functions [21,111].

Likewise, studies have reported GDF15 as a clock-controlled gene with a nominal diurnal circadian rhythmicity in human serum, and the GFRAL receptor being expressed in the hippocampus, spinal cord, and thalamus regions of the brainstem, NTS and area postrema (AP), which are associated with the suprachiasmatic nucleus (SCN), aka master circadian clock, solidifies the possibility of a connection [12,91,114,122-124]. Therefore, applying chronotherapy strategies in the GDF15 therapeutic undertaking might be beneficial to determine a specific time of the day to administer GDF15, such that it produces a precise effect with no or minimal side effects.

Also, a study on endometriosis found that GDF15 is not increased in the serum of people with endometriosis, but it is in the peritoneal fluid. And that GDF15 levels in the peritoneal fluid were positively correlated with endometriosis severity. So, it seems that GDF15 levels might act locally and not be picked up by a blood test.

So, I'm thinking that maybe GDF15 levels are a downstream result in ME/CFS (cell/ER stress?), but that perhaps some people react particularly badly to the levels, resulting in a severe ME/CFS state with similarities to hyperemesis gravidarum. Marlena Fejzo described an illness involving extreme exhaustion, no doubt partly due to undernutrition and dehydration but perhaps also caused more directly by the GDF15.

 

[SNT Gatchaman]

We don't know enough about GDF15 but it sounds as if it's not as simple as too much or too little. A few passages relating to GDF15 in ME/LC or unrelated papers.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts (2023, Science Translational Medicine) —

Unexpectedly, however, mitochondrial gene expression was down-regulated in the cerebella and strongly induced in the striata of the hamster brains. The absence of viral effects on lung mitochondrial gene expression where viral RNA was high compared with robust changes in mitochondrial gene expression in the brain where viral RNA was absent raised the possibility that modulation of energy metabolism in distant tissues might be because of ISR [integrated stress response] activation producing diffusible factors such as GDF15, which could potentially modulate mitochondrial function in tissues far from the initial site of infection.

Intracellular to Interorgan Mitochondrial Communication in Striated Muscle in Health and Disease (2023, Endocrine Reviews) —

Myomitokines, such as FGF21, GDF15, and mtDNA, can alter whole-body physiology and systemic responses

Upon activation of the integrated stress response, CHOP and ATF4 regulate the transcription of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two metabolic hormones with autocrine, paracrine, and endocrine actions. Muscle-derived FGF21 and GDF15 are systemic mediators of the integrated stress response, and mediate the communication between cardiac and skeletal muscle with distant organs upon mitochondrial stress

Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor β (TGF-β) superfamily with pleiotropic functions. GDF15 expression in striated muscle increases with different stresses and stimuli, including mitochondrial dysfunction and the mitochondrial unfolding protein response and integrated stress response. GDF15 in striated muscle acts locally through autocrine/paracrine signaling or spreads from muscles to other organs in an endocrine fashion. As with FGF21, the outcome of GDF15 critically depends on the capacity of the myomitokines to overcome the stress condition and restore homeostasis. Therefore, skeletal muscle GDF15 induction can be associated with improved mitochondrial function, or it can be associated with chronic mitochondrial dysfunction.

Implications of mitochondrial fusion and fission in skeletal muscle mass and health (2023, Seminars in Cell & Developmental Biology) —

Muscle-specific genetic disruption of mitochondrial fusion, fission, or both result in cell-autonomous mitochondrial dysfunction, ER stress, and atrophy as well as cell-non-autonomous systemic responses mediated by muscle-release of the nuclear-encoded myokines FGF21 and GDF15.

Since FGF21 or GDF15 circulating levels can be associated with both beneficial and detrimental effects, it is unlikely that these myokines are detrimental per se, and they cannot be considered a biomarker of disease alone. Therefore, another explanation of the discrepancies of FGF21 and GDF15 on aging and survival is that inflammation might synergize with the myokines in senescence induction.

 

[Sid]

I don’t have any experience of pregnancy but I will say nausea is a major ME/CFS symptom for me triggered by exertion. Very embarrassing in public especially.

This thread is horrifying overall. Without even reading the original article I just knew some BPSer was going to say that it’s all due to subconscious fear of pregnancy.

 

[Midnattsol]

This is a 20 minute listen and the backstory is highly relevant to the historical and current ME/CFS research situation. Following her discovery (against the wind and tide of grant reviewers and medical misogyny) she now hopes for treatment trials. One of those is using metformin to increase GDF15 levels prior to pregnancy to de-sensitise Mum prior to the fetus producing it.

(Edit: sync-post with Hutan)

I haven't listened so this might not be relevant, but metformin can cross the placenta and could thus influence fetal development. Currently metformin use during pregnancy is associated with small-for-gestational age at birth and childhood obesity. The father's use of metformin around time of conception has also been implicated in long-term health outcomes of the child, so this could possibly be true for mothers as well.

Metformin use in pregnancy: What about long-term effects in offspring?

 

[SNT Gatchaman]

I presume the idea would be to stop metformin during the pregnancy itself, once maternal baseline GDF15 levels have been elevated.

 

[Ash]

Gosh, aren't women in the 21st century so lucky that kind of attitude no longer exists, and that being female is no longer seen as predisposing to hysterical conversion.

Oh wait, it does...

…