glp1 mimetics  (Mimetics)

Journal: Gastro Hep Advances

Article Title: Cannabinoids Block Fat-induced Incretin Release via CB 1 -dependent and CB 1 -independent Pathways in Intestinal Epithelium

doi: 10.1016/j.gastha.2024.07.006

Figure Lengend Snippet: Exogenous activation of peripheral CB 1 Rs blocks fat-induced GIP and aGLP1 secretion. Compared to the control (0.5 mL saline by oral gavage and vehicle by IP injection), corn oil (CO; 0.5 mL by oral gavage) increased levels of the incretins GIP [treatment effect F (3,17) = 10.53, P = .0004] (A) and active GLP1 [treatment effect F (3,17) = 18.06, P < .0001] (B) but did not significantly increase levels of plasma insulin (C) in plasma of fasted mice. This effect was blocked by pretreatment with CB 1 R agonist, WIN 55,212-2 (WIN, IP 3 mg per kg 30 minutes before CO). The inhibitory effects of WIN on incretins were inhibited by coadministration with the peripherally-restricted CB 1 R antagonist, AM6545 (AM; IP 10 mg per kg 30 minutes before CO). Data expressed as means ± S.E.M. and analyzed by one-way ANOVA with post hoc Holm-Sidak multiple comparison tests. n = 4–6 per condition, ∗ P < .05, ∗∗ P < .01, ∗∗∗ P < .001.

Article Snippet: Indeed, GLP1 mimetics (eg, semaglutide, liraglutide) reduce body mass in obese and diabetic patients, partly due to the hypophagic effects of activating GLP1 receptors.

Techniques: Activation Assay, Control, Saline, Injection, Clinical Proteomics, Comparison

Journal: Cell Reports Medicine

Article Title: Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes

doi: 10.1016/j.xcrm.2022.100813

Figure Lengend Snippet: GLP1 signaling elevates circulating IL-6 activating STAT3 in preadipocytes (A) Postprandial effects of exenatide. Baseline plasma was collected, immediately followed by subcutaneous injection of exenatide or placebo, immediately followed by a meal. Plasma was collected again 2 h after baseline collection. IL-6, insulin, FFA, and glucose levels were measured at both time points. ∗p < 0.01 (Student’s t test); n = 16. Shown are mean values ± SEM. (B) Liraglutide induces IL-6 secretion by human leukocytes. Human PBMCs were seeded at 2 × 10 6 cells/0.2 mL/well of RPMI 1640 containing 10% fetal bovine serum (FBS) onto a 48-well plate. After 24 h, medium and non-adherent cells were removed. Adherent monocytes were washed and treated with 200 μL RPMI 1640 medium containing 100 ng/mL of LPS or 100 nM liraglutide for 12 h. The supernatants were collected and IL-6 was measured. Shown are mean values ± SEM. ∗∗p < 0.001, Student’s t test. (C) Human SAT preadipocytes were seeded at 5 × 10 5 cells/well of 10% FBS DMEM medium onto a 12-well plate. After 24 h, medium was removed, and the cells were washed with PBS and maintained in 1% FBS DMEM overnight. Cells were then treated with 20 ng/mL of human IL-6, collected at the indicated time points, and subjected to immunoblotting with the indicated antibodies. Graph: quantification of band intensity normalized to actin. ∗p < 0.001, Student’s t test.

Article Snippet: A number of GLP1 mimetics, including liraglutide, exenatide, and dulaglutide, have been developed for metronomic administration and sustained release in patients., Incretin mimetics also have anti-obesity effects that are not completely understood.

Techniques: Clinical Proteomics, Injection, Western Blot

Journal: Cell Reports Medicine

Article Title: Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes

doi: 10.1016/j.xcrm.2022.100813

Figure Lengend Snippet: Liraglutide induces IL-6 signaling and adipocyte browning in mice (A) Mouse immortalized brown pre-adipocytes seeded at confluency were induced for brown adipogenesis in DMEM/10% fetal bovine serum (FBS) medium containing 50 nM insulin/0.5 mM IBMX, 1 μM dexamethasone, 1 nM 3,5,3′-Triiodothyronine (T3), and 5 μM rosiglitazone for 24 h, were washed and cultured in DMEM/10% FBS medium containing 500 pg/mL mouse IL-6, 100 nM liraglutide, or their combination, for 6 and 24 h. UCP1 expression was measured by western blotting. Arrow: UCP1; ns, nonspecific band. Graph: quantification of band intensity normalized to actin. Shown are mean values ± SEM. ∗p < 0.001, one-way ANOVA. (B) HFD-fed overweight C57BL/6 females (n = 3) were injected with a single s.c. dose of liraglutide (0.4 mg/kg BW). Plasma was collected at indicated time points after administration and IL-6 levels were measured by ELISA. Shown are mean values ± SEM. ∗p < 0.001, one-way ANOVA. (C) Left: Echo MRI analysis of HFD-fed overweight C57BL/6 males after 2 and 4 weeks of liraglutide, treatment (0.2 mg/kg) shows a reduction of fat mass in liraglutide-treated mice. Right: mass of isolated individual AT depots at week 4. n = 5. ∗p = 0.05, Student’s t test. (D) Cold tolerance test in mice from experiment (C) at week 4. ∗p < 0.05, Student’s t test. (E) Analysis of SAT, VAT, and BAT sections from mice in (C) at week 4. Increased UCP1 expression is indicated (arrows). Adipocytes are revealed by perilipin-1 (PLN1) IF. Nuclei are blue. Scale bar, 50 μm. (F) Quantification of data from (E). ∗p < 0.05, Student’s t test. (G) Analysis of VAT from mice in (C) at week 4 by RT-PCR showing relative UCP1 expression (normalized to 18S RNA) increased by liraglutide (Lira). (H) Analysis of VAT from mice in (C) at week 4 by immunoblotting with the indicated antibodies in two mice per group (randomly selected) showing liraglutide-increased UCP1 and pAMPK signal. (I) Nine-week-old C57BL/6 males were injected with a single s.c. dose of liraglutide (0.2 mg/kg BW). Analysis of SAT and VAT by RT-PCR after 30 min shows liraglutide-increased relative SOCS3 and ADAM10 expression (normalized to 18S RNA). ∗p < 0.05, ∗∗p < 0.01, Student’s t test. (J) C57BL/6 males were injected with a single s.c. dose of liraglutide (0.2 mg/kg BW). Analysis of VAT by immunoblotting shows liraglutide-induced pAMPK and pSTAT3 peaking at 120 min and decreasing at 240 min post-injection.

Article Snippet: A number of GLP1 mimetics, including liraglutide, exenatide, and dulaglutide, have been developed for metronomic administration and sustained release in patients., Incretin mimetics also have anti-obesity effects that are not completely understood.

Techniques: Cell Culture, Expressing, Western Blot, Injection, Clinical Proteomics, Enzyme-linked Immunosorbent Assay, Isolation, Reverse Transcription Polymerase Chain Reaction

Journal: Cell Reports Medicine

Article Title: Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes

doi: 10.1016/j.xcrm.2022.100813

Figure Lengend Snippet: Liraglutide-induced AT beiging is suppressed by IL-6-blocking antibody (A) Echo MRI analysis of HFD-fed overweight C57BL/6 males after 4 weeks of treatment with liraglutide (0.2 mg/kg), IL-6 antibody (5 mg/kg), or a combination of liraglutide and IL-6 antibody at doses above. Note that IL-6 antibody suppresses weight loss. ∗p < 0.05, one-way ANOVA. (B) Analysis of VAT from mice in (A) at week 4 by immunoblotting with the indicated antibodies in randomly selected mice. Note that liraglutide-induced pSTAT3 is suppressed by IL-6 antibody. (C) Analysis of VAT from mice in (A) at week 4 by RT-PCR shows that liraglutide-induced UCP1 expression (normalized to 18S RNA) is suppressed by IL-6 antibody. Shown is mean ± SEM, n = 4, ∗p < 0.05, one-way ANOVA. (D) Analysis of SAT and VAT sections from mice in (A) at week 4. UCP1 expression (arrows) induced by liraglutide (Lira) is suppressed by IL-6 antibody. Adipocytes are revealed by perilipin-1 (PLN1) IF. Nuclei are blue. Scale bar, 50 μm. Graphs: the corresponding IF quantifications; ∗p < 0.05, one-way ANOVA. (E) Analysis of mice in (A) at week 4 by cold tolerance test. Liraglutide-induced increase in body temperature maintenance (∗p < 0.05 compared to PBS group, one-way ANOVA) is suppressed by IL-6 antibody. Plotted is core body temperature decrease from baseline (at 0 min at 4°C). (F) Analysis of mice in (A) at week 4 by glucose tolerance test. Liraglutide-induced decrease in circulating glucose (∗p < 0.05 compared to PBS group, one-way ANOVA) is suppressed by IL-6 antibody. AUC, area under the curve for each group.

Article Snippet: A number of GLP1 mimetics, including liraglutide, exenatide, and dulaglutide, have been developed for metronomic administration and sustained release in patients., Incretin mimetics also have anti-obesity effects that are not completely understood.

Techniques: Blocking Assay, Western Blot, Reverse Transcription Polymerase Chain Reaction, Expressing

Journal: Cell Reports Medicine

Article Title: Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes

doi: 10.1016/j.xcrm.2022.100813

Figure Lengend Snippet: IL-6R KO in adipocyte progenitors negates the thermogenic effect of liraglutide (A) Paraffin sections of AT from WT and Pdgfrb-Cre; IL-6R fl/fl (KO) mice subjected to IF. Note that IL-6R protein expression (green) in PDGFRβ-positive ASCs (red, resulting in yellow signal in WT mice) is lost in ASC but not in PDGFRβ-negative endothelium of KO mice. a, adipocytes. Scale bar, 50 μm. (B) Echo MRI analysis of HFD-fed overweight C57BL/6 and KO males and females after 4 weeks of liraglutide, treatment. Note the reduction of fat mass in both WT and KO liraglutide-treated mice. n = 5. ∗p < 0.05, Student’s t test. (C) Cold tolerance test in mice from (B) at week 4. Note that liraglutide-induced improvement in body temperature maintenance is not observed in KO mice (∗p < 0.05 for WT + PBS versus WT + Liraglutide, one-way ANOVA). (D) Analysis of AT sections from mice in (B) at week 4. Note that liraglutide-induced UCP1 expression increase (arrows) is not observed in SAT and reduced in BAT of KO mice. Adipocytes are revealed by perilipin-1 (PLN1) IF. Nuclei are blue. Scale bar, 50 μm. Graphs: the corresponding IF quantifications; ∗p < 0.05, one-way ANOVA. (E) Analysis of mice in (B) at week 4 by glucose tolerance test. Liraglutide-induced decrease in circulating glucose (∗p < 0.05 compared with PBS group, one-way ANOVA) is reduced in KO mice. AUC, area under the curve for each female group. (F) Respiratory exchange ratio (RER = VCO 2 /VO 2 ) in mice from experiment in (B) at week 4. Average night and day plots show a significant decrease by liraglutide in WT mice, and an increase in KO mice.

Article Snippet: A number of GLP1 mimetics, including liraglutide, exenatide, and dulaglutide, have been developed for metronomic administration and sustained release in patients., Incretin mimetics also have anti-obesity effects that are not completely understood.

Techniques: Expressing