Journal Article Review Epublish
PubMed: 40806735 DOI: 10.3390/ijms26157611
Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.
Int J Mol Sci 26(15)
Authors: Minju Seo, Seung Yeon Pyeon, Man S Kim
Affiliations
- Translational-Transdisciplinary Research Center, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul 05278, Republic of Korea. Department of Medicine, Kyung Hee University School of Medicine, Seoul 02453, Republic of Korea.
- Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul 05278, Republic of Korea.
Abstract
The relationship between metabolic dysfunction and mental health disorders is complex and has received increasing attention. This review integrates current research to explore how stress-related growth differentiation factor 15 (GDF15) signaling, ceramides derived from gut microbiota, and mitochondrial dysfunction in the brain interact to influence both metabolic and psychiatric conditions. Evidence suggests that these pathways converge to regulate brain energy homeostasis through feedback mechanisms involving the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. GDF15 emerges as a key stress-responsive biomarker that links peripheral metabolism with brainstem GDNF family receptor alpha-like (GFRAL)-mediated anxiety circuits. Meanwhile, ceramides impair hippocampal mitochondrial function via membrane incorporation and disruption of the respiratory chain. These disruptions may contribute to sustained pathological states such as depression, anxiety, and cognitive dysfunction. Although direct mechanistic data are limited, integrating these pathways provides a conceptual framework for understanding metabolic-psychiatric comorbidities. Furthermore, differences in age, sex, and genetics may influence these systems, highlighting the need for personalized interventions. Targeting mitochondrial function, GDF15-GFRAL signaling, and gut microbiota composition may offer new therapeutic strategies. This integrative perspective helps conceptualize how metabolic and psychiatric mechanisms interact for understanding the pathophysiology of metabolic and psychiatric comorbidities and highlights therapeutic targets for precision medicine.
MeSH
Depression, Comorbidity, Homeostasis, Stress, Physiological, Brain, Mitochondria, Biomarkers, Ceramides, Precision Medicine, Therapeutics, Gastrointestinal Microbiome, Mental Health, Microbiota