Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

Abstract

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

The Impact of CB1 Receptor on Inflammation in Skeletal Muscle Cells

“…[21][22][23] Furthermore, investigations in both animals and humans have found that cannabinoids have also been connected with type II diabetes and obesity. 26 Cannabinoids and CB1 receptor modulation do, however, influence downstream inflammatory pathways, in particular IL-6 in several tissues. 27,28 Cannabinoid modulates several inflammatory cells, such as gastrointestinal inflammation.…”

Quantitation of Synthetic Cannabinoid Receptor Agonists in Postmortem Blood Using a Single Point Calibration

“…This is not the first time SCRA have been linked to hyperglycemia (31) or even DKA (32). Given the wide heterogeneity of SCRA and their metabolites, as well as the role of CB 1 in insulin resistance (33), it is possible that some SCRA could lead to DKA in susceptible individuals. Again, without the pathologists report, it is not possible for us to pass comment on our cases, but this is an area that requires further research.…”

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…Cannabinoid type 1 receptors (CB1R), an important element of this system, are expressed most densely in the brain but are also present at functionally relevant levels in many peripheral tissues . Research has shown that activation of CB1R increases appetite, insulin resistance, and hepatic lipogenesis, whereas blockade of peripheral CB1R ameliorates obesity and its metabolic consequences . Chronic treatment with rimonabant, the first globally acting CB1R antagonist, has been shown to reduce body weight and improve cardiometabolic risk factors in rats with obesity and humans with overweight/obesity .…”