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

Arulkumar Nagappan,Myeong Ho Jung,Jooyeon Shin

doi:10.3390/ijms20092109

Arulkumar Nagappan, Myeong Ho Jung + Show 1 more

Open Access

https://doi.org/10.3390/ijms20092109

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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.

Highlights

Insulin resistance is a pathological condition characterized by the inability of insulin to regulate glucose and lipid metabolism in peripheral tissues even when insulin concentrations in the blood are elevated [1,2]
An enhanced expression of CB1R is observed in the hepatic cells, which contributes to the hepatic insulin resistance, fibrosis, lipogenesis, and steatosis
It should be noted that CB1R-deficient mice are resistant to obesity and metabolic syndrome, and CREBH is a target of CB1R in the regulation of hepatic insulin resistance

Summary

Introduction

Insulin resistance is a pathological condition characterized by the inability of insulin to regulate glucose and lipid metabolism in peripheral tissues even when insulin concentrations in the blood are elevated [1,2]. Receptor activation leads to phosphorylation of key tyrosine residues on IRSs that allows for association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K) through its SRC homology 2 (SH2) domains (APS protein) [17]. Once activated, this protein creates suitable binding sites for IRSs that are activated via phosphorylation by various insulin-induced kinases such as protein kinase C (PKC), serine/threonine-protein kinase 2 (SIK2), protein kinase B (AKT), p70 ribosomal protein S6 kinase 1. AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 (GSK3) are insulin-independent kinases that phosphorylate IRSs and trigger downstream signal transduction [18]. Insulin activates non-IRS-dependent signaling pathways by other substrates such as heterotrimeric G proteins and the son of sevenless (SOS) growth factor [20]

Insulin Resistance

Distribution and Biological Roles of CB1R in the Human Body

Participation of CB1R in Obesity and Insulin Resistance

The Functions of CB1R in Pancreatic β-Cells and Skeletal Muscle

The Therapeutic Potential

Conclusions