Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets

Abstract

Aims/hypothesisThe cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism.MethodsWe generated a beta cell specific Cnr1 (CB1R) knockout mouse (β-CB1R−/−) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961.Resultsβ-CB1R−/− mice had increased fasting (153 ± 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 ± 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high-fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from β-CB1R−/− mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells.Conclusions/interpretationOur data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes.

The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

“…Similar observations were also obtained in STZ-induced diabetic mice by another group (15). Importantly, cannabinoids and cannabinoid receptors have been previously shown to modulate islet viability in DIO mice (36,37). Herein, we also found a significant reduction in oxidative stress in pancreas isolated from HFD-Abn-CBD mice compared to HFD-vehicle mice.…”

3D quantification of changes in pancreatic islets in mouse models of diabetes type I and II

“…The corresponds to previous studies showing that beta cell proliferation is the main factor driving the expansion of beta cell volume in response to S961 dosing (Dumayne et al, 2020;Jiao et al, 2014;Yi et al, 2013). Similarly, increased islet number in S961 treated mice has also been observed by other (González-Mariscal et al, 2018;Okamoto et al, 2017). However, these results do not rule out alternative mechanisms resulting in increased beta cell count and volume.…”

Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics

“…mCB1A and mCB1B probes (green) hybridize with mCB1R (red) positive cells in hippocampus (a mCB1A; b mCB1B) and cortex (c mCB1A; d mCB1B). Yellow arrows indicate the colocalization of mCB1 isoforms with the common mCB1 probe contrast to wild-type mice [36]. We now report that mCB1A and mCB1B were upregulated in the hypothalamus, hippocampus, cortex, and skeletal muscles of the β-CB1R −/− mice (Fig.…”