The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

Abstract

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut–brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

“…Intriguingly, as shown in Figure 2 , both positive and negative changes in their effects may occur under the same pathological condition (described in detail previously by [ 6 , 9 , 11 , 12 , 13 , 14 ]). Thus, CB 1 R activation may have beneficial effects against loss of appetite and body weight, nausea, spasticity in multiple sclerosis, pain (especially peripherally-restricted CB 1 R agonists), anxiety- and depressive-like behavior, posttraumatic stress disorder, neuroprotection, and epilepsy [ 9 , 15 , 16 , 17 , 18 ] or may lead to vasodilatation in arteries of hypertensive animals [ 19 , 20 ]. THC itself (international non-proprietary name, dronabinol), its synthetic analog nabilone, and the mixture of THC and cannabidiol (nabiximols) are approved by the US Food and Drug Administration and other national or supranational drug agencies for some of the above indications ( Table 1 [ 21 ]).…”

“…THC itself (international non-proprietary name, dronabinol), its synthetic analog nabilone, and the mixture of THC and cannabidiol (nabiximols) are approved by the US Food and Drug Administration and other national or supranational drug agencies for some of the above indications ( Table 1 [ 21 ]). However, CB 1 R activation can also lead to cognitive impairment, agitation and acute psychosis [ 22 , 23 ], vasodilatation and/or hypotension in various forms of shock, decreased cardiac function (cardiomyopathies, and heart failure), diet-induced obesity, development of non-alcoholic fatty liver disease and peripheral insulin resistance [ 6 , 7 , 9 , 15 ]. Deleterious consequences of the activation CB 1 Rs result from their ability to increase reactive oxygen species (ROS) generation and pro-inflammatory responses leading to endothelial and cardiomyocyte cell remodeling/fibrosis, death, and cardiovascular, metabolic, renal, respiratory, and hepatic dysfunction, detected in both preclinical and clinical studies [ 6 , 9 , 11 , 13 , 15 , 24 ].…”

“…However, CB 1 R activation can also lead to cognitive impairment, agitation and acute psychosis [ 22 , 23 ], vasodilatation and/or hypotension in various forms of shock, decreased cardiac function (cardiomyopathies, and heart failure), diet-induced obesity, development of non-alcoholic fatty liver disease and peripheral insulin resistance [ 6 , 7 , 9 , 15 ]. Deleterious consequences of the activation CB 1 Rs result from their ability to increase reactive oxygen species (ROS) generation and pro-inflammatory responses leading to endothelial and cardiomyocyte cell remodeling/fibrosis, death, and cardiovascular, metabolic, renal, respiratory, and hepatic dysfunction, detected in both preclinical and clinical studies [ 6 , 9 , 11 , 13 , 15 , 24 ]. In addition to the agonists mentioned above, one CB 1 R antagonist, rimonabant, was available until 2008 as an anti-obesity drug ( Table 1 ).…”

“…In this respect, CB 1 R antagonists are interesting and are discussed as future drug strategies for the treatment of diabetes [ 86 , 87 ], chronic kidney disease [ 88 ], fatty liver disease [ 89 ], alcohol use disorder [ 86 ], and COVID-19 [ 90 ]. The CB 1 R antagonist rimonabant was used as an anti-obesity drug [ 15 , 86 , 91 ] but withdrawn from the market in 2008 because of severe central side effects [ 86 ]. Second-generation CB 1 R antagonists (e.g., AM6545, JD5037), peripherally restricted, may offer advantages over rimonabant.…”

Cannabis use as a factor of lower corpulence in hepatitis C-infected patients: results from the ANRS CO22 Hepather cohort

“…One possible explanation for the relationship between cannabis use and corpulence is that such frequent use may downregulate cannabinoid receptor 1 (CB1)—which regulates appetite and body weight, thereby reducing energy storage and increasing metabolic rates (Clark et al 2018 ; Spindle et al 2021 ). In two preclinical studies, CB1 antagonists and peripherally restricted CB1 antagonists (i.e., with no effect on the central nervous system) showed some efficacy on obesity and metabolic syndrome (O’Sullivan et al 2021 ; Lopez Trinidad et al 2021 ).…”