Synergistic activation of colonic endocrine cells through nutrient receptors is an important target for metabolic regulation in adults with obesity, according to a study published in Gut.
Colonic enteroendocrine cells (EECs) store and release anorectic hormones that are key regulators of satiety. EECs express multiple nutrient sensing receptors, particularly for the medium-chain fatty acids (MCFAs) GPR84 and FFAR4. Researchers have proposed a nonsurgical approach with targeted colonic delivery of MCFAs, which induce EECs and neuronal activation leading to anorectic effects.
To study this effect, investigators conducted a randomized, double-blind, placebo-controlled, cross-over study (ClinicalTrials.gov Identifier: NCT04292236) in adults with obesity. Participants were given combined GPR84 and FFAR4 agonists in colonic release capsules before meals. The researchers measured serum hormones, energy intake, and appetite perception. Additionally, cell type, activation by agonists, and hormone/serotonin release were determined in human colonic explants. Mouse colonic afferent nerve responses to nutrients/mediators were recorded via electrophysiology.
The researchers found that administering a colonic release formulation of MCFAs, normally found only in the upper gut, before meals reduced food intake and boosted plasma peptide YY in adults with obesity, without causing adverse effects. In addition, researchers found that MCFAs cooperatively stimulated nutrient receptors that synergize through different intracellular pathways in EECs to maximize hormone release. This action on colonic EECs induces synergistic activation of afferent nerves projecting to the central nervous system.
This study is not without limitations. Authors noted the need for longer time points for measuring hormone release and effects on appetite perception.
“In conclusion, we demonstrate that specific targeting of multiple nutrient-sensing receptors stimulates convergent activation of EEC and colonic afferent endings,” stated the authors. They added, “Importantly, we show that targeting colonic L cells by costimulating specific receptors in obese volunteers has the capacity to reduce food intake and boost [peptide YY] levels, thereby supporting our preclinical findings and offering the potential development of a novel and effective obesity treatment without the drawbacks of surgery.”
Peiris M, Aktar R, Reed D, et al. Decoy bypass for appetite suppression in obese adults: role of synergistic nutrient sensing receptors GPR84 and FFAR4 on colonic endocrine cells. Gut. Published online June 3, 2021. doi:10.1136/gutjnl-2020-323219