Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Abstract

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 CB 1 cannabinoid receptor (CB 1 R) 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 CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R 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 CB 1 R −/− 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.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

Immunohistochemistry detected and localized cannabinoid receptor type 2 in bovine fetal pancreas at late gestation

“…In conclusion, given the distribution patterns we detected, we hypothesize that the cannabinoid molecules are implicated in control of gland functioning as already observed and demonstrated in laboratory animals, 8 probably by acting on some endocrine cells, epithelial excretory ducts and on small arterial vessel walls as the cannabinoid CB2 receptor was detected in these sites.…”

“…Moreover, a recent study evidenced the importance of endocannabinoids in the control of cell proliferation and organization, with a particular look to the fetal pancreas development. 8 However, the expression of the components of the endocannabinoid system in the pancreas still needs to be elucidated because often there is no consensus on its distribution in the endocrine islets, for which descriptions are starkly contrasting, especially between animals of different species, such as rats and mice. 9 , 10 Moreover, in human pancreas the CB2 receptor was also found in the exocrine pancreas, unlike what had been previously reported for laboratory animals.…”

A TRPV 1‐to‐secretagogin regulatory axis controls pancreatic β‐cell survival by modulating protein turnover

“…Pancreatic band a-cells express key enzymes for anandamide metabolism (Akiba et al, 2004;Malenczyk et al, 2013Malenczyk et al, , 2015. Moreover, substantial levels of circulating anandamide are found in blood (Matias et al, 2006).…”

“…Therefore, we searched for Ca 2+ permeable channels that (i) can work independently or in tandem with glucose-regulated voltage-gated Ca 2+ channels, which are lowly expressed in b-cells (Rorsman & Trube, 1986), (ii) their phasic activity can fine-tune b-cell Ca 2+ A-A 2 Transcriptome analysis (bulk) of human (n = 202) pancreatic islets reveals decreased secretagogin (SCGN) expression in patients with type 2 diabetes (T2D; A). An appealing candidate satisfying the above criteria is the transient receptor potential (TRP) family of channels, which are evolutionarily conserved in the endocrine lineage, Ca 2+ permeable, and their genetic ablation is implicated in tissue size control (Zhao et al, 2013;Riera et al, 2014;Malenczyk et al, 2015). Conversely, secretagogin mRNA levels positively correlate with insulin expression (A 2 ).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…In the fetal pancreas, CB1 signaling is very important for regulating the spatial organization of both ␣ and ␤ cells, as shown by pharmacological blockade of CB1 or DAGL␣ (523). MAGL knockout mice show an unchanged size of pancreatic islet but an increased number of ␣ cells per islet.…”