Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture.
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.
Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden; Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria;
Katarzyna
K
Malenczyk
Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria;
Erik
E
Keimpema
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, I-80078 Pozzuoli, Naples, Italy;
Fabiana
F
Piscitelli
Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden;
Daniela
D
Calvigioni
Department of Surgical Sciences, Uppsala University, SE-75185 Uppsala, Sweden;
Peyman
P
Björklund
Department of Psychological and Brain Sciences, Gill Center for Neuroscience, Indiana University, Bloomington, IN 47405;
Kenneth
K
Mackie
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, I-80078 Pozzuoli, Naples, Italy;
Vincenzo
V
Di Marzo
Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden tibor.harkany@meduniwien.ac.at tomas.hokfelt@ki.se.
Tomas G M
TG
Hökfelt
Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;
Agnieszka
A
Dobrzyn
Division of Molecular Neurobiology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria; tibor.harkany@meduniwien.ac.at tomas.hokfelt@ki.se.
Tibor
T
Harkany
D000704:Analysis of Variance; D000818:Animals; D063388:Endocannabinoids / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005260:Female; D005333:Fetus / Q000378:metabolism; D005951:Glucose Tolerance Test; D007091:Image Processing, Computer-Assisted; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D011247:Pregnancy; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
D063388:Endocannabinoids; D015525:Fatty Acids, Omega-3; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse
G protein-coupled receptor; cell adhesion; diabetes; migration; proliferation