Journal: Molecular Metabolism

Article Title: Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues

doi: 10.1016/j.molmet.2026.102327

Figure Lengend Snippet: A Glp1r encoding AAV induces expression of a functional receptor in the liver of DIO GLP-1R knockout mice. Global GLP-1R knockout mice on HFD were dosed I.V. with a control AAV (black bars or circles) or mouse Glp1r expressing AAV at 10 11 genome copies (GC) per mouse (light red bars or circles) or 10 12 GC per mouse (dark red bars or circles). ( A ) Glp1r gene expression relative to beta-actin in the epididymal white adipose tissue (eWAT), brown adipose tissue (BAT), liver (LV), and hypothalamus (HT). ( B ) Blood glucose after a single semaglutide dose (3 nmol/kg). ( C,D ) Body weight change and cumulative food intake (FI) in response to the Glp1r expressing AAV alone dosed on day 0. ( E,F,G ) Body weight change, cumulative FI, and body composition (day 27) in response to the Glp1r expressing AAV + semaglutide (QD, SC 3 nmol/kg started day 13). ( H ) Correlation between hepatic Glp1r expression and semaglutide mediated weight loss. All data are presented as mean ± SEM. ∗ indicates a p-value ≤0.05 compared to control AAV-treated animals or control AAV-treated groups. Notations under/over time points indicate significant difference at that time point determined by 2way ANOVA with Dunnet's test (panel A) or Tukey multiple comparisons test (all others). Notations to the right of the data indicate a significant group effect determined by 2way ANOVA with Tukey multiple comparisons.

Article Snippet: The Taqman probes used are against Glp1r (ThermoFisher, Mm00445292_m1) as the gene of interest, and Beta Actin (ThermoFisher, 4352341E ) as the endogenous control.

Techniques: Expressing, Functional Assay, Knock-Out, Control, Gene Expression

Journal: Molecular Metabolism

Article Title: Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues

doi: 10.1016/j.molmet.2026.102327

Figure Lengend Snippet: Coupling ectopic, hepatic Glp1r expression and semaglutide treatment enhances weight loss in DIO mice. WT DIO mice were dosed with a Glp1r expressing AAV (10 12 GC) on day −7, then with semaglutide (dose escalated from 1 to 100 nmol/kg) from day 0–56. ( A,B ) BW loss and cumulative FI. ( C,D ) Lean and fat mass loss on days 0, 5 and 12. ( E ) Acute EE response to semaglutide (3 nmol/kg) in WT DIO mice dosed with either control or Glp1r AAV. ( F,G ) Blood glucose during IPGTTs performed on day 0 (F) and day 56 (G). ( H,I ) Heart rate and mean arterial pressure assessed in control AAV and Glp1r AAV treated mice in response to semaglutide (0.5, 1, and 3 nmol/kg SC doses). ( J ) In vitro GLP-1R internalization induced by native GLP-1 or semaglutide. ( K ) In vivo PK profile for semaglutide in WT DIO mice dosed with either control AAV (closed circles) or Glp1r expressing AAV (10 12 GC, open circles). All data are presented as mean ± SEM. ∗ indicates a p-value ≤0.05 compared to respective control animals. ˆ indicates a p-value ≤0.05 between control AAV + semaglutide and Glp1r AAV + semaglutide groups. Notations under/over time points indicate significant difference at that time point determined by 2way ANOVA with Tukey multiple comparisons test. Notations to the right of the data indicate a significant group effect determined by 2-way ANOVA with Tukey multiple comparisons.

Article Snippet: The Taqman probes used are against Glp1r (ThermoFisher, Mm00445292_m1) as the gene of interest, and Beta Actin (ThermoFisher, 4352341E ) as the endogenous control.

Techniques: Expressing, Control, In Vitro, In Vivo

Journal: Molecular Metabolism

Article Title: Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues

doi: 10.1016/j.molmet.2026.102327

Figure Lengend Snippet: A GLP-1R agonist that exhibits limited receptor internalization can obviate the PK liability of hepatic Glp1r expression. ( A ) In vitro GLP-1R internalization induced by native GLP-1 and NNC5840. ( B ) In vivo PK profile for semaglutide or NNC5480 in WT DIO mice dosed with either control or Glp1r expressing AAV (10 12 GC). ( C,D ) Weight loss and cumulative FI during a 14 day treatment regimen with either vehicle, semaglutide, or a NNC5480 in WT DIO mice dosed with either control AAV or Glp1r expressing AAV (10 12 GC). ( E ) Acute EE response to NNC5480 (3 nmol/kg) in WT DIO mice dosed with either control or Glp1r AAV. ( F ) Blood glucose during an I.P. glucose tolerance test performed on day 0. All data are presented as mean ± SEM. ∗ indicates a p-value ≤0.05 compared to respective control animals. ˆ indicates a p-value ≤0.05 between groups as indicated. ο indicates a p-value ≤0.05 for all groups compared to their respective controls. x indicates a p-value ≤0.05 between control AAV + semaglutide and Glp1r AAV + semaglutide groups. Notations under/over time points indicate significant difference at that time point determined by 2way ANOVA with Tukey multiple comparisons test. Notations to the right of the data indicate a significant group effect determined by 2way ANOVA with Tukey multiple comparisons.

Article Snippet: The Taqman probes used are against Glp1r (ThermoFisher, Mm00445292_m1) as the gene of interest, and Beta Actin (ThermoFisher, 4352341E ) as the endogenous control.

Techniques: Expressing, In Vitro, In Vivo, Control

Journal: Molecular Metabolism

Article Title: Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues

doi: 10.1016/j.molmet.2026.102327

Figure Lengend Snippet: The weight lowering efficacy of a dual incretin agonist is enhanced in the presence of ectopic, hepatic Glp1r expression. ( A ) In vitro GLP-1R internalization for native GLP-1 and a dual GLP-1R/GIPR agonist. ( B,C ) Weight loss and cumulative FI during a 14 day treatment regimen with either vehicle or a dual GLP-1R/GIPR agonist at 1 nmol/kg in control AAV or Glp1r AAV treated mice. ( D ) Acute EE response to a dual GLP-1R/GIPR agonist (1 nmol/kg) in WT DIO mice dosed with either control or Glp1r AAV. ( E ) Blood glucose during an IPGTT on day 14 of the study. ( F,G ) Acute HR and MAP response to a dual GLP-1R/GIPR agonist in control AAV and Glp1r AAV treated mice. All data are presented as mean ± SEM. ∗ indicates a p-value ≤0.05 compared to respective control animals. ˆ indicates a p-value ≤0.05 between control AAV + GLP-1R/GIPR agonist and Glp1r AAV + GLP-1R/GIPR agonist groups. Notations under/over time points indicate significant difference at that time point determined by 2way ANOVA with Tukey multiple comparisons test. Notations to the right of the data indicate a significant group effect determined by 2way ANOVA with Tukey multiple comparisons.

Article Snippet: The Taqman probes used are against Glp1r (ThermoFisher, Mm00445292_m1) as the gene of interest, and Beta Actin (ThermoFisher, 4352341E ) as the endogenous control.

Techniques: Expressing, In Vitro, Control