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. 2023 Aug:74:101765.
doi: 10.1016/j.molmet.2023.101765. Epub 2023 Jun 28.

Effects of a long-acting secretin peptide analog alone and in combination with a GLP-1R agonist in a diet-induced obesity mouse model

Mona Loeffler  1 , Katarina Klepac  2 , Angela Baljuls  3 , Bradford Hamilton  4 , Svenja Mayer-Wrangowski  5 , Peter Haebel  6 , Tina Zimmermann  7
Affiliations

Effects of a long-acting secretin peptide analog alone and in combination with a GLP-1R agonist in a diet-induced obesity mouse model

Mona Loeffler et al. Mol Metab. 2023 Aug.

Abstract

Objective: Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity.

Methods: BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist.

Results: BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss.

Conclusions: BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.

Keywords: Combination therapy; Obesity; Peptide treatment; Secretin.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Figures

Figure 1
Figure 1
Structures of hSecretin and the lipidated secretin analogue BI-3434.
Figure 2
Figure 2
In vitro potency and lipolysis assay of BI-3434 and native secretin. Representative concentration-response curves showing cAMP accumulation in cells stably expressing human SCTR after activation with human secretin (A) and BI-3434 (B). Summary of EC50 values for tested compounds (C), refers to A and B. Dose-response curves showing the glycerol levels of differentiated murine adipocytes treated with native secretin, BI-3434, and isoproterenol (D). Summary of EC50 values for tested compounds (E), refers to D.
Figure 3
Figure 3
Acute target engagement of BI-3434 in lean mice. Cumulative food intake after a single injection of stapled secretin (A) or BI-3434 (B) (n = 8–10/group). Plasma glucagon levels measured at Cmax (2 h after injection) of BI-3434 (C). Luciferase expression in the cAMP reporter CRE-Luc mouse (n = 6/group) treated with BI-3434 (D). Data are shown as mean ± SEM. Statistical analysis was done using one-way ANOVA followed by Dunnett’s method for multiple comparisons versus vehicle with significance defined at ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
Figure 4
Figure 4
Subchronic efficacy of BI-3434 in DIO mice. Percentage change in body weight from baseline (A) and food intake changes (B) over time in DIO mice (n = 8/group) treated bi-daily s.c. with 300 nmol/kg BI-3434. Fat mass measured by quantitative nuclear magnetic resonance at the end of study (C). Changes in energy expenditure of DIO mice treated with 300 nmol/kg BI-3434 over time (D) and average EE quantified over 24 h (E) (ANOVA with repeated measures [treatment × time, p = 0.02]). EE in dark (F) and light (G) phase quantified over 24 h (ANOVA with repeated measures [treatment × time, p = 0.04] versus vehicle with significance defined at ∗p < 0.05 during the dark phase). Liver triglycerides (H) and plasma glucagon (I) levels measured at the end of the study. Data are shown as mean ± SEM. Statistical analysis was done using unpaired Student’s t-test with significance defined at ∗p < 0.05.
Figure 5
Figure 5
Combination study of BI-3434 with GLP-1R agonist in DIO mice. Percentage change in body weight from baseline until day 28 in DIO mice (n = 8–10/group) treated bi-daily s.c. with 300 nmol/kg BI-3434 and/or 10 nmol/kg Semaglutide (A). Effects of BI-3434 and/or Semaglutide on food intake over the period of the study (B). Fat mass measured by quantitative nuclear magnetic resonance at the end of study (C). Energy expenditure shown over 48 h for DIO mice treated with BI-3434 and/or Semaglutide (D). Mean energy expenditure plotted against body weight. (E). EE in dark (F) and light (G) phase. Concentrations of blood glucose (H), liver triglycerides (I) and plasma active ghrelin (J) on day 28. Plasma levels of pancreatic enzymes lipase (K) and amylase (L) on day 28. Data are shown as mean ± SEM. Statistical analysis was done using one-way ANOVA followed by Dunnett’s method for multiple comparisons or ANCOVA with body weight as a covariate versus vehicle with significance defined at ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 vs vehicle; ##p < 0.01 vs 10 nmol/kg semaglutide.
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