Article

Effects of Chronic Oral Rimonabant Administration on Energy Budgets of Diet-Induced Obese C57BL/6 Mice

Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
Obesity (Impact Factor: 3.73). 12/2011; 20(5):954-62. DOI: 10.1038/oby.2011.357
Source: PubMed

ABSTRACT

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure. To examine the effects of rimonabant on components of energy balance, we administered rimonabant or its vehicle to diet-induced obese (DIO) C57BL/6 mice once daily for 30 days, by oral gavage. Rimonabant induced a persistent weight reduction and a significant decrease in body fatness across all depots. In addition to transiently reduced food intake, rimonabant-treated mice exhibited decreased apparent energy absorption efficiency (AEAE), reduced metabolizable energy intake (MEI), and increased daily energy expenditure (DEE) on days 4-6 of treatment. However, these effects on the energy budget had disappeared by days 22-24 of treatment. No chronic group differences in resting metabolic rate (RMR) or respiratory quotient (RQ) (P > 0.05) were detected. Rimonabant treatment significantly increased daily physical activity (PA) levels both acutely and chronically. The increase in PA was attributed to elevated activity during the light phase but not during the dark phase. Taken together, these data suggested that rimonabant caused a negative energy balance by acting on both energy intake and expenditure. In the short term, the effect included both reduced intake and elevated PA but the chronic effect was only on increased PA expenditure.

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Available from: John Speakman, Sep 19, 2014
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    • "Rimonabant does not alter parameters of energy expenditure in young and aged mice Next, we explored the possibility that the observed reductions in body mass in response to rimonabant may also be associated with increased systemic energy expenditure (Zhang et al., 2012). For example, rimonabant has been previously reported to increase energy expenditure in diet-induced obese C57BL/6 mice (Zhang et al., 2012). However as shown in Fig. 2, neither physical activity (Fig. 2A and B), body temperature (Fig. 2C and D) or resting metabolic rate (RMR) (Fig. 2E and F), were significantly altered by rimonabant treatment in young and aged mice. "
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    ABSTRACT: The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant-mediated insulin sensitization in aged adipose tissue coincided with amelioration of low-grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging-related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging.
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    • "Metabolic effects of various anti-obesity drugs compared to either ad libitum or pair-fed controls are widely described [1] [2]. Although both drug-treated and pair-fed groups experience energy deficit, only paired feeding involves food restriction, i.e. prolonged or increased hunger. "
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    • "Amongst synthetic cannabinoid agents discovered for various pharmaceutical applications, both CB1 neutral antagonists and CB1 inverse agonists have been successfully adopted in weight control in obesity animal models [6] [7] [8] [9] [10]. In addition, improvement of cardiovascular risk factors has been also determined by the pleiotropic activity of these compounds [10] [11] [12]. "
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