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Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism

OBJECTIVE: The gastrointestinal tract affects physiological activities and behavior by secreting hormones and generating signals through the activation of nutrient sensors. GPR119, a lipid sensor, is indirectly involved in the secretion of incretins, such as glucagon-like peptide-1 and glucose-depen...

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Autores principales: Igarashi, Miki, Hayakawa, Tetsuhiko, Tanabe, Haruka, Watanabe, Keita, Nishida, Akari, Kimura, Ikuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771719/
https://www.ncbi.nlm.nih.gov/pubmed/36462626
http://dx.doi.org/10.1016/j.molmet.2022.101649
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author Igarashi, Miki
Hayakawa, Tetsuhiko
Tanabe, Haruka
Watanabe, Keita
Nishida, Akari
Kimura, Ikuo
author_facet Igarashi, Miki
Hayakawa, Tetsuhiko
Tanabe, Haruka
Watanabe, Keita
Nishida, Akari
Kimura, Ikuo
author_sort Igarashi, Miki
collection PubMed
description OBJECTIVE: The gastrointestinal tract affects physiological activities and behavior by secreting hormones and generating signals through the activation of nutrient sensors. GPR119, a lipid sensor, is indirectly involved in the secretion of incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by enteroendocrine cells, while it directly stimulates insulin secretion by pancreatic beta cells. Since GPR119 has the potential to modulate metabolic homeostasis in obesity and diabetes, it has attracted interest as a therapeutic target. However, previous studies have shown that the deletion of Gpr119 in mice does not affect glucose homeostasis and appetite in either basal or high-fat diet-fed conditions. Therefore, the present study aimed to explore the role of GPR119 signaling system in energy metabolism and feeding behavior in mice. METHODS: Gpr119 knockout (KO) mice were generated using CRISPR-Cas9 gene-editing technology, and their feeding behavior and energy metabolism were evaluated and compared with those of wild type (WT) mice. RESULTS: Upon inducing metabolic stress via food deprivation, Gpr119 KO mice exhibited lower blood glucose levels and a higher body weight reduction compared to WT mice. Although food intake in WT and KO mice were similar under free-feeding conditions, Gpr119 KO mice exhibited increased food intake when they were refed after 24 h of food deprivation. Further, food-deprived Gpr119 KO mice presented shorter post-meal intervals and lower satiety for second and later meals during refeeding, resulting in increased food intake. Associated with this meal pattern, levels of oleoylethanolamide (OEA), an endogenous agonist of GPR119, in the luminal contents of the distal gastrointestinal tract were elevated within 2 h after refeeding. The large-intestinal infusion of OEA prolonged post-meal intervals and increased satiety in the first meal, but not the second meal. On the other hand, infusion of oleic acid increased cecal OEA levels at 2 h from the beginning of infusion, while prolonging post-meal intervals and increasing satiety on the meals that occurred approximately 2 h after the infusion. Cecal OEA levels were low in antibiotic-treated mice, suggesting that the gut microbiota partially synthesizes OEA from oleic acid. CONCLUSIONS: Collectively, our results indicate that the activation of gastrointestinal GPR119 by microbiota-produced OEA derived from oleic acid is associated with satiety control and energy homeostasis under energy shortage conditions.
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spelling pubmed-97717192022-12-23 Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism Igarashi, Miki Hayakawa, Tetsuhiko Tanabe, Haruka Watanabe, Keita Nishida, Akari Kimura, Ikuo Mol Metab Original Article OBJECTIVE: The gastrointestinal tract affects physiological activities and behavior by secreting hormones and generating signals through the activation of nutrient sensors. GPR119, a lipid sensor, is indirectly involved in the secretion of incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by enteroendocrine cells, while it directly stimulates insulin secretion by pancreatic beta cells. Since GPR119 has the potential to modulate metabolic homeostasis in obesity and diabetes, it has attracted interest as a therapeutic target. However, previous studies have shown that the deletion of Gpr119 in mice does not affect glucose homeostasis and appetite in either basal or high-fat diet-fed conditions. Therefore, the present study aimed to explore the role of GPR119 signaling system in energy metabolism and feeding behavior in mice. METHODS: Gpr119 knockout (KO) mice were generated using CRISPR-Cas9 gene-editing technology, and their feeding behavior and energy metabolism were evaluated and compared with those of wild type (WT) mice. RESULTS: Upon inducing metabolic stress via food deprivation, Gpr119 KO mice exhibited lower blood glucose levels and a higher body weight reduction compared to WT mice. Although food intake in WT and KO mice were similar under free-feeding conditions, Gpr119 KO mice exhibited increased food intake when they were refed after 24 h of food deprivation. Further, food-deprived Gpr119 KO mice presented shorter post-meal intervals and lower satiety for second and later meals during refeeding, resulting in increased food intake. Associated with this meal pattern, levels of oleoylethanolamide (OEA), an endogenous agonist of GPR119, in the luminal contents of the distal gastrointestinal tract were elevated within 2 h after refeeding. The large-intestinal infusion of OEA prolonged post-meal intervals and increased satiety in the first meal, but not the second meal. On the other hand, infusion of oleic acid increased cecal OEA levels at 2 h from the beginning of infusion, while prolonging post-meal intervals and increasing satiety on the meals that occurred approximately 2 h after the infusion. Cecal OEA levels were low in antibiotic-treated mice, suggesting that the gut microbiota partially synthesizes OEA from oleic acid. CONCLUSIONS: Collectively, our results indicate that the activation of gastrointestinal GPR119 by microbiota-produced OEA derived from oleic acid is associated with satiety control and energy homeostasis under energy shortage conditions. Elsevier 2022-11-30 /pmc/articles/PMC9771719/ /pubmed/36462626 http://dx.doi.org/10.1016/j.molmet.2022.101649 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Igarashi, Miki
Hayakawa, Tetsuhiko
Tanabe, Haruka
Watanabe, Keita
Nishida, Akari
Kimura, Ikuo
Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title_full Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title_fullStr Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title_full_unstemmed Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title_short Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
title_sort intestinal gpr119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771719/
https://www.ncbi.nlm.nih.gov/pubmed/36462626
http://dx.doi.org/10.1016/j.molmet.2022.101649
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