Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice

Abstract

The cannabinoid receptor 2 (CB2) is well known for its immune modulatory role. However, recent localisation of CB2 receptors in metabolically active tissue suggests that the CB2 receptor plays a significant role in energy homeostasis. This study was designed to investigate the impact of chronic CB2 receptor stimulation on food intake, body weight and mood. Lean male C57BL/6 mice were injected i.p. with the selective CB2 receptor agonist, JWH-015 (0.0, 1.0, 5.0 and 10.0 mg kg-1) to establish dose response parameters. Mice made obese following exposure to a diet consisting of 19.4 MJ/kg (4641 Kcal/kg) of energy (19.0% protein, 21.0% total fat, 4.7% crude fiber, and 4.7% AD fiber were given either vehicle or 10 mg/kg JWH-015. Impact on mood, food intake, body weight, plasma metabolites, expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT), and markers of inflammation were measured. High dose (10 mg/kg) JWH-015 reduced food intake after 1, 2, 4, and 24 h in lean mice. When given to diet induced obese (DIO) mice, a 10 mg/kg dose of JWH-015 significantly reduced body weight compared to vehicle. This dose led to a shift in markers of lipid metabolism and inflammation in WAT consistent with lipolysis and improved immune response. Furthermore, JWH-015 (10 mg/kg) produced a transient reduction in food intake and significant reduction in fat mass and adipocyte cell size. Importantly, JWH-015 produced an anxiolytic response in the elevated plus maze while having no effect on immobility time in the forced swim test. It should be noted that though the 10 mg/kg dose produced positive effects on the obese state, the possibility that these effects are mediated via non-CB2 receptor mechanisms cannot be ruled out. These results demonstrate a role for CB2 receptors in modulating energy homeostasis and obesity associated metabolic pathologies in the absence of any adverse impact on mood.

Central and peripheral control of food intake

“…CB2 is well known in his immune modulatory eff ect (Cabral and Griffi nTh omas 2009). However, recently it has been found that CB2 plays a role in the energy homeostasis and food intake (Verty et al 2015) (Figure 3).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…However, although acute ⌬ 9 -THC produces hyperphagic effects in rats (393) and mice (34), chronic administration of the compound does not result in increased body weight. This might be due to 1) the capability of ⌬ 9 -THC to desensitize CB1 receptors, to induce aversive responses, or to act as a partial agonist/antagonist in vivo (212); 2) the different contribution of CB1 on glutamatergic or GABAergic terminals to produce hyperphagic or hypophagic effects, respectively, as shown through the use of conditional CB1 knockout mice lacking CB1 in either population of neurons (55); and 3) the recent finding that CB2 receptor activation instead reduces body weight and fat mass in obese mice (881). Peripheral effects were also described.…”

Cannabinoid Receptor 2 as Antiobesity Target: Inflammation, Fat Storage, and Browning Modulation

“…A common CB2 variant, Q63R, causing reduced CB2 function, has been associated with eating disorders in humans (20). CB2 agonists reduce food intake in lean mice (20) and improve both body weight and obesity-associated inflammation in diet-induced obese mice (21). Moreover, CB2 genetic ablation results in adiposity (22).…”