Fig. 4: A schematic overview of the proposed BDNF-TrkB-FRS3 signaling pathway, its role in energy balance regulation, and its connection to the leptin-melanocortin pathway.

Key anorexigenic components are illustrated in dark blue for the leptin-melanocortin pathway and lighter blue for the BDNF-TrkB-FRS3 pathway. Pointed arrows between the components represent activation of downstream proteins, where whole pointed arrows indicate that the linking mechanisms are well-established and dotted pointed arrows indicate that mechanisms remain to be clarified. The leptin-melanocortin pathway is activated in response to increased leptin levels and other hormones in the feeding state, resulting in decreased appetite and food intake, increased energy expenditure, and lower BMI. It also has an inhibiting mechanism, illustrated in light blue to the left, where AGRP acts as an antagonist of MC4R in response to low leptin levels with food deprivation, resulting in MC4R inhibition, increased appetite, decreased energy expenditure, and higher BMI. The BDNF-TrkB pathway is thought to be activated downstream of the leptin-melanocortin pathway to mediate its effect on energy balance. We postulate that FRS3 is a link in the undiscovered downstream signaling cascade of BDNF and TrkB. Components of these pathways are associated with both monogenic and polygenic forms of obesity, with the supporting evidence summarized to the right in the figure. Created in BioRender. Aegisdottir, H. (2025) https://BioRender.com/ a25a422. LEPR leptin receptor, AGRP agouti-related protein, POMC pro-opiomelanocortin, α-MSH α-melanocyte stimulating hormone, PCSK1 proprotein convertase subtilisin/kexin type 1, pLoF predicted loss-of-function, MC4R melanocortin 4 receptor, BDNF, brain derived neurotrophic factor, TrkB tropomyosin receptor kinase B, FRS3 fibroblast growth factor receptor substrate 3, EAF effect allele frequency.