Growth Differentiation Factor 15 Induces Gastric Fundus Contraction Involving Cholinergic Excitation: Morphofunctional Evidence in Rodent Models

Growth Differentiation Factor 15 (GDF15) is a peptide from the transforming growth factor (TGF)-β superfamily, typically found at low levels in mammalian tissues, but significantly upregulated during cellular stress or injury. Initially recognised for its role in inducing anorexia and vomiting, GDF15 is now seen as a broader regulator of homeostasis, although its effects on gastrointestinal function remain unclear. This study examined GDF15's impact on the gastric fundus, a key region for appetite regulation. In ex vivo rodent gastric smooth muscle, GDF15 receptors were detected, and exposure to GDF15 caused smooth muscle depolarization, leading to increased mechanical activation. Morphological analyses revealed changes in the contractile apparatus, resembling cholinergic excitatory pathways. These effects were blocked by atropine, indicating muscarinic receptor involvement. Taken together, these findings suggest that GDF15 enhances gastric contractility by influencing cholinergic tone. Further studies will shed light on its mechanism of action and on the potential translational perspective of current results, elucidating whether elevated plasma levels of GDF15 observed in several physiological and pathological conditions can also have repercussions in gastric physiology, appetite regulation and weight loss.