Regulation, Function, and Dysregulation of Endocannabinoids in Models of Adipose and β-Pancreatic Cells and in Obesity and Hyperglycemia

Abstract

Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…Matias et al 60 reported that a CB1R agonist stimulates glucose-dependent insulin secretion (GDIS) in rat insulinoma RIN-m5F cells. These results would predict that inverse agonists should inhibit glucose-dependent insulin release.…”

“…These results would predict that inverse agonists should inhibit glucose-dependent insulin release. Given that rimonabant has been shown to improve glycemic control in diabetic patients, the prediction of Matias et al 60 is counter-intuitive as many anti-diabetic agents such as GLP-1 are known to stimulate GDIS.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Many of the biological actions of the ECS are mediated through G‐protein‐coupled cannabinoid type 1 (CB1R) and type 2 (CB2R) receptors which can be activated by several endogenous ligands, including anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG). Importantly, ECS dysregulation has been linked to abdominal obesity and other risk factors for type 2 diabetes (Engeli et al ., 2005; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006).…”

“…Importantly, ECS dysregulation has been linked to abdominal obesity and other risk factors for type 2 diabetes (Engeli et al ., 2005; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). Furthermore, increased circulating levels of AEA and 2‐AG, as well as elevated levels of 2‐AG within visceral adipose tissue, have been reported in obese and/or hyperglycaemic type 2 diabetic patients (Bluher et al ., 2006; Matias et al ., 2006).…”

“…For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). Furthermore, increased circulating levels of AEA and 2‐AG, as well as elevated levels of 2‐AG within visceral adipose tissue, have been reported in obese and/or hyperglycaemic type 2 diabetic patients (Bluher et al ., 2006; Matias et al ., 2006). In accord with this, hyperactivation of CB1R‐induced signalling has been implicated in numerous metabolic abnormalities including hyperphagia, insulin resistance, glucose intolerance and impaired lipid homeostasis (Engeli et al ., 2005; Jbilo et al ., 2005; Osei‐Hyiaman et al ., 2005).…”