GDF-15/GFRAL Axis Dynamics and Vulnerability Windows in Bariatric Surgery: Pathophysiological, Microbiomic, and Pharmacological Perspectives

Bariatric surgery (BS) and new pharmacological treatments cause significant neurometabolic changes. However, the pathways linking peripheral stress to central metabolic control remain poorly understood. This review highlights the GDF-15/GFRAL/RET complex as a key integrator of multiorgan-to-brain stress signals that shape systemic metabolic adaptation after surgical and pharmacological interventions. Based on a structured search across PubMed, Embase, Scopus, Google Scholar, and Web of Science covering 2020–2026 alongside foundational studies, we integrated translational evidence from peer-reviewed human trials and mechanistic animal models to map the GDF-15/GFRAL/RET axis across bariatric and incretin domains. We examined the neurobiology of the GDF-15/GFRAL axis to clarify variability in metabolic and behavioral outcomes after BS. This axis links metabolic stress signals from the gut, liver, and adipose tissue to the hindbrain and hypothalamic regulation of energy balance. Changes in the gut microbiome and SCFA–FFAR2/FFAR3 signaling after surgery interact with GDF-15 and incretin pathways. Future studies should critically compare BS with synergistic or alternative non-invasive neurometabolic approaches such as incretin mimetics, exogenous GDF-15 therapies, and high-protein diets.