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. 2020 Jun 1:220:112870.
doi: 10.1016/j.physbeh.2020.112870. Epub 2020 Mar 14.

Hindbrain melanocortin 3/4 receptors modulate the food intake and body weight suppressive effects of the GLP-1 receptor agonist, liraglutide

Samantha M Fortin  1 , Jack Chen  2 , Matthew R Hayes  3
Affiliations

Hindbrain melanocortin 3/4 receptors modulate the food intake and body weight suppressive effects of the GLP-1 receptor agonist, liraglutide

Samantha M Fortin et al. Physiol Behav. .

Abstract

Simultaneously targeting multiple energy balance control systems is a promising direction for the development of obesity pharmacotherapies. Here, we explore the interaction between the GLP-1 and melanocortin system within the dorsal vagal complex (DVC) of the caudal brainstem. Using a pharmacological approach, we demonstrate that the full anorectic potential of liraglutide, an FDA-approved GLP-1 analog for the treatment of obesity, requires DVC melanocortin 3/4 receptor (MC3/4R) signaling. Specifically, the food intake and body weight suppressive effects of liraglutide were attenuated by DVC administration of the MC3/4R antagonist SHU9119. In contrast, the anorectic effects of liraglutide were enhanced by combined activation of DVC MC3/4Rs using the agonist MTII. Our findings highlight the modulation of liraglutide-induced anorexia by DVC MC3/4R signaling, thereby suggesting a site of action at which two important energy balance control systems interact.

Keywords: Area postrema; Brainstem; MSH; NTS; Obesity; POMC.

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Conflict of interest statement

Declaration of Competing Interest MRH also receives research funding from Zealand Pharma, Eli Lilly & Co., Novo Nordisk and Boehringer Ingelheim that was not used in support of these studies. All other authors declare no competing interests.

Figures

Fig 1.
Fig 1.
Cumulative chow intake (A) and change in body weight (B) at 1, 4, 24, 48 hours (hr) post-administration of vehicle (veh) or Shu9119 (20 pmol; intra-DVC) followed by vehicle or liraglutide (lirag; 100 μg/kg; IP). Data are expressed as mean ± SEM. Different letters indicate significant differences between groups (p<0.05).
Fig 2.
Fig 2.
Dose-dependent effects of DVC-directed MTII on food intake (A) and body weight (B) at 1, 4, 24, 48 hours (hr) post-administration of vehicle (veh) or MTII (1 or 5 pmol; intra-DVC). Data are expressed as mean ± SEM. Different letters indicate significant differences between groups (p<0.05).
Fig 3.
Fig 3.
Cumulative chow intake (A) and change in body weight (B) at 1, 4, 24, 48 hours (hr) post-administration of vehicle (veh) or MTII (1 pmol; intra-DVC) followed by vehicle (veh) or liraglutide (lirag; 50 μg/kg; IP). Data are expressed as mean ± SEM. Different letters indicate significant differences between groups (p<0.05).
See this image and copyright information in PMC

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