BDNF-related brain–liver communication in metabolic syndrome: implications for anxiety and depression

Metabolic syndrome is frequently accompanied by anxiety and depression, suggesting interactions between metabolic dysfunction and affective regulation. Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin receptor kinase B (TrkB) are involved in energy balance, neuroplasticity, stress adaptation, and emotional processing, positioning BDNF-related signaling as a potential interface within brain-liver communication. Experimental evidence strongly supports central BDNF-TrkB signaling in the regulation of feeding and energy expenditure, while central BDNF-sensitive pathways can also influence hepatic glucose production. Conversely, obesity and metabolic dysfunction alter the systemic lipid, endocrine, inflammatory, vascular, and neural environment, which can impair hypothalamic and hippocampal BDNF-related signaling. These processes occur within a broader neuro-metabolic network involving the liver, adipose tissue, gut, skeletal muscle, immune system, and vasculature rather than through a liver-specific pathway. Chronic stress, anxiety, and depression further intersect with metabolic dysfunction through partly distinct neuroendocrine and neuroplastic mechanisms, including hypothalamic-pituitary-adrenal axis and glucocorticoid signaling. Glucagon-like peptide-1 signaling represents an additional interface between metabolic regulation and central neuroplasticity, although the contribution of BDNF to its hepatic and neurobehavioral effects remains incompletely defined. Key uncertainties include the functional significance of liver-associated and circulating BDNF, BDNF-defined autonomic pathways to the liver, genetic variation, and tissue-specific therapeutic targeting. Future studies integrating circuit- and tissue-specific manipulation, standardized BDNF measurements, both sexes, and longitudinal human phenotyping are needed to distinguish causal mechanisms from associative relationships.