Capozzi, M. | bioRxiv Science

bioRxiv2025

Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.

ObjectiveUnimolecular triagonists drive substantial weight loss in patients with obesity (PwO) by engaging the glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) receptors to reduce food intake (FI) and the hepatic glucagon (Gcg) receptor to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R monoagonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. MethodsWe used an attenuated adenovirus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. ResultsAgonism of the ectopic GLP-1R with either semaglutide, a low internalization GLP-1R agonist (Sema584), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to agonist treatment alone. ConclusionsThis represents a novel mechanism for achieving polypharmacy to treat obesity. HighlightsO_LIA Glp1r encoding AAV induces expression of a functional receptor mouse livers. C_LIO_LIEndogenous GLP-1R does not mediate semaglutide clearance. C_LIO_LIEctopic GLP-1R mediates semaglutide clearance. C_LIO_LIEctopic, hepatic Glp1r plus semaglutide enhances weight loss in mice. C_LIO_LIEctopic, hepatic Glp1r plus a dual incretin agonist enhances weight loss in mice. C_LI

zoology↗

bioRxiv2025

Identification of QTLs linked to partial resistance to foot and root rot caused by Fusarium avenaceum and Fusarium oxysporum in faba bean (Vicia faba)

Foot and root rot, caused by a complex of soil-borne fungal and oomycete pathogens, including several Fusarium spp., can cause serious yield losses in faba bean. Current control strategies rely largely on agronomic practices and limited varietal resistance. Identifying novel sources of genetic resistance is of great potential value for breeding elite varieties with improved foot rot resistance. A partially resistant Vicia faba accession ig124213 (NV490) was crossed with a moderately susceptible ig124301 (NV512) and a mapping population comprising 198 F3 families was developed. This was screened for resistance to a mixture of seven UK field isolates of Fusarium avenaceum and Fusarium oxysporum under glasshouse conditions. Several F3 families with moderate to high levels of resistance to both Fusarium species were identified, and a high-density linkage map of the V. faba genome including 6755 SNP-markers in seven linkage groups (LG) was generated using the Vfaba_v2 Axiom SNP array. Quantitative trait loci associated with improved resistance to Fusarium foot and root rot were identified, including one major QTL on LG4, corresponding to the chromosome 4 of V. faba. Key messageThe first QTL associated with partial resistance to Fusarium foot and root rot has been identified using a biparental mapping population of Vicia faba.

plant biology↗