Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 45, Pages E6185-E6194Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519040112
Keywords
cell adhesion; diabetes; G protein-coupled receptor; migration; proliferation
Categories
Funding
- Foundation for Polish Science [TEAM/2010-5/2, MPD/2009/4]
- National Science Center [UMO-2011/03/B/NZ4/03055, UMO-2013/10/E/NZ3/00670]
- National Institutes of Health [DA023214, DA011322, DA021696]
- Swedish Research Council
- Hjarnfonden
- Petrus and Augusta Hedlunds Foundation
- Novo Nordisk Foundation
- Visby Scholarship Program
- Karolinska Institutet-National Institutes of Health Training Program in Neuroscience grant
- Alzheimers Research UK [ART-EG2009A-1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0010695, NNF15OC0015964] Funding Source: researchfish
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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 a cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of beta 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 alpha/beta cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB(1)Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in omega-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.
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