CellsOct 16, 2026

Changes in the GDF-15/GFRAL System and Sensitive Periods After Weight-Loss Surgery: Body, Gut Bacteria, and Drug Perspectives

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 17, 2026

Abstract

The GDF-15/GFRAL/RET complex is identified as a key integrator of stress signals affecting metabolic adaptation after bariatric surgery and pharmacological treatments.

Bariatric surgery and new medications may lead to significant changes in neurometabolic processes.
The GDF-15/GFRAL/RET axis connects metabolic stress signals from organs like the gut, liver, and fat tissue to brain centers that regulate energy balance.
Variability in metabolic and behavioral outcomes after bariatric surgery may be influenced by the neurobiology of the GDF-15/GFRAL axis.
Alterations in gut microbiome composition and specific signaling pathways after surgery may interact with GDF-15 and incretin mechanisms.

Simplified

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.

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Changes in the GDF-15/GFRAL System and Sensitive Periods After Weight-Loss Surgery: Body, Gut Bacteria, and Drug Perspectives

Abstract

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