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.
Highlights
The endogenous cannabinoid system has long been known as a potent modulator of appetite. [1] Most of this work has focused on the role of the cannabinoid receptor 1 (CB1) in food intake and energy homeostasis
In order to explore the mechanisms via which JWH-015 would affect lipolysis in the retroperitoneal white adipose tissue (rWAT), we examined the expression of the cyclic AMP dependent protein kinase A (PKA) regulatory subunit RIIβ
The major findings of this study demonstrate for the first time that chronic administration of a CB2 receptor agonist produces a profound reduction in body weight gain in diet-induced obese (DIO) mice despite only a transient reduction in food intake and no change in UCP1 expression in brown adipose tissue (BAT)
Summary
The endogenous cannabinoid system has long been known as a potent modulator of appetite. [1] Most of this work has focused on the role of the cannabinoid receptor 1 (CB1) in food intake and energy homeostasis. Compounds that reduce endogenous CB1 receptor activity such as rimonabant [7] reduce appetite [8] and body weight in lean [9, 10] and diet-induced obese (DIO) [11, 12] rodents via a mechanism that involves increased energy expenditure [12]. Given the positive role of rimonabant on obesity, this drug was considered a promising antiobesity pharmacotherapy. This promise was short lived and rimonabant was withdrawn from the market due its adverse psychiatric impact related to increased anxiety/depression and suicidal ideation [13, 14]
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