Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 45, E6185-E6194 p.Article in journal (Refereed) Published
Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R(-/-) islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.
Place, publisher, year, edition, pages
2015. Vol. 112, no 45, E6185-E6194 p.
cell adhesion; diabetes; G protein-coupled receptor; migration; proliferation
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-266638DOI: 10.1073/pnas.1519040112ISI: 000364470300016PubMedID: 26494286OAI: oai:DiVA.org:uu-266638DiVA: diva2:868350
FunderSwedish Research CouncilThe Swedish Brain FoundationNovo NordiskThe Karolinska Institutet's Research Foundation