GDF15 is still a mystery hormone, 2025, Casper M. Sigvardsen et al

Highlights
The plasma concentration of growth differentiation factor 15 (GDF15) varies tremendously, from 0.2–0.5 ng/ml in healthy young individuals at rest to up to 2 ng/ml after prolonged hard exercise. GDF15 concentrations may rise to 1–2 ng/ml in older individuals and those with obesity, may reach 10 ng/ml in conditions such as cancer and cardiovascular disease, and may increase to 20 ng/ml during pregnancy.

Rodent experimental models frequently involve injecting large doses of recombinant human GDF15, increasing endogenous GDF15 secretion through gene overexpression or mitochondrial defects such as Crif1 knockout, or using human GDF15 secreted by inoculated human cancer cell lines. However, the impact of moderate endogenous overexpression remains unclear.

In humans, plasma GDF15 concentration is inversely correlated with physical fitness level and may be considered a marker of poor health.

In rodents, GDF15 reduces appetite and promotes weight loss while also enhancing insulin sensitivity independently of weight loss.
Dietary regulation of GDF15 is minor, but GDF15 may increase glucose-stimulated insulin secretion.
A GDF15-related capped peptide (CAP-GDF15) decreases appetite in mice.

Abstract
Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. Despite its identification over 20 years ago, the functions of GDF15 remain complex and not fully elucidated.

Its concentration in plasma varies widely depending on the physiological and pathophysiological state of the organism. GDF15 has been described to regulate food intake and insulin sensitivity in rodents via the GDNF family receptor α-like (GFRAL) receptor, and to be elevated in pregnancy and many disease states and decreased in physically fit individuals.

We discuss the latest developments in the regulation of GDF15 secretion and its diverse physiological effects, and touch upon possible GFRAL-independent effects of GDF15. In addition, we discuss the effects of proteins and peptides derived from the same precursor protein as GDF15.
LINK

 

Concluding remarks and future perspectives
GDF15 displays large variations in plasma concentration during different physiological and pathophysiological conditions, suggesting that it plays important but potentially different roles in the body. However, the data evaluating its function are difficult to synthesize due to extremely different experimental protocols.

What is perplexing is that in some situations GDF15 seems to be beneficial (e.g., longevity with overexpression, increased insulin sensitivity) while in other situations it is detrimental (e.g., cancer cachexia). Perhaps this relates to the magnitude of the increase or fluctuation versus constantly increased concentrations in cachexia.

Moreover, a moderate increase in plasma GDF15 under physiological stress or in disease might be considered an adaptive response aiming at resolving stress or partially controlling the disease as proposed [3]. A unique situation is pregnancy, where concentrations in plasma are increased around 100–200-fold from basal level without causing cachexia and in most cases causing only transient nausea.

Perhaps the effect of GDF15 is regulated by increases in placental hormones such as human chorion gonadotropin (hCG) or other pregnancy-stimulated hormones which are not present in cancer cachexia. Modulating GDF15 effects by other hormones is ripe for further investigation.

It is also intriguing to see increasing reports of GFRAL-independent effects of GDF15 suggesting that GDF15 may engage receptors other than the GFRAL receptor which, however, is undisputed for effects on appetite. Finally, the extent to which various forms of pro-GDF15 fragments are circulating and whether they have any effects is not known and needs to be resolved. GDF15 is still a mystery hormone.