Central mechanisms underlying the synergistic anorectic effect of CCK and GLP-1 combination therapy

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Combination therapies that enhance the effects of separate peptides while limiting adverse effects constitute a promising strategy to improve the efficacy of pharmacologic-based treatments of diabetes and obesity. Cholecystokinin (CCK) and Glucagon-like peptide-1 (GLP-1) are gut hormones produced in response to meal ingestion that promote satiety and meal termination. Co-infusion of long-acting CCK and GLP-1 receptor agonists have been shown to synergistically reduce food intake and body-weight in diet-induced obese rats. However, the mechanisms by which CCK and GLP-1 interact remain mostly unknown. The objective of this dissertation is to investigate for the first time the central mechanisms underlying the synergistic anorectic effect of CCK and GLP-1 combination therapy. We characterized feeding behaviour in response to the administration of CCK receptor (CCK-R) and a GLP-1 receptor (GLP-1R) agonists in lean mice. We found that the GLP-1R agonist potentiates the acute anorectic response of CCK-R agonists, providing a model of acute anorexia in lean mice for the study of the associated central mechanisms. Using immunohistochemistry against the marker of neuronal activation cfos, we identified brain nuclei that may be involved in the potentiation. Using immunofluorescence, we investigated the role of POMC, NPY, TH and GLP-1R expressing neurons in the potentiation. While we found that GLP-1R and TH neurons might modestly participate in the potentiated anorectic effect, other neuronal cell populations might be involved. We used phosphorylated ribosome capture to generate hypothesis about the molecular signature of neurons activated or inhibited in response to CCK-R and/or GLP-1R agonists. In particular, we identified Calcrl expressing neurons of the nucleus of the solitary tract that stood out as strong candidates in the mediation of the potentiated anorectic response to the combination therapy. Our work constitutes the first attempt to understand the mechanisms by which CCK-R and GLP-1R agonists synergistically reduce food intake. We uncovered several promising leads that will need to be further explored in future research.

Blouet, Clemence
CCK, GLP-1, combination, satiety, neuroanatomy, synergy, energy metabolism, food intake, c-fos, immunohistochemistry, phosphorylated ribosome capture, pTRAP, cholecystokinin, glucagon-like peptide-1, obesity
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge