Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

Abstract

Background and objectives:The antiobesity effects of suppressed endocannabinoid signaling may rely, at least in part, on changes in lipid fluxes. As fatty acids exert specific effects depending on their level of saturation, we hypothesized that the dietary fatty acid composition would influence the outcome of treatment with a CB 1 -receptor antagonist (rimonabant). Methods: Mice were treated with rimonabant (10 mg kg À1 body weight per day) or vehicle while equicalorically fed either a low-fat diet (LF), a high-fat (HF) diet or an HF diet in which 10% of the saturated fatty acids (SFAs) were replaced by polyunsaturated fatty acids (PUFA) from fish oil (FO). Food intake and body weight were registered daily. Indirect calorimetry was performed and feces were collected. After 3 weeks, mice were killed for blood and tissue collection. Results: Relative to the LF diet, the HF diet caused anticipated metabolic derangements, which were partly reversed by the HF/FO diet. The HF/FO diet, however, was most obesity-promoting despite inhibiting lipogenesis as indicated by low gene expression levels of lipogenic enzymes. On all three diets, rimonabant treatment improved metabolic derangements and led to significantly lower body weight gain than their respective controls. This latter effect appeared largest in the HF/FO group, but occurred without major changes in nutrient absorption and energy expenditure. Conclusion: The effects of chronic rimonabant treatment on body weight gain occurred irrespective of diet-induced changes in lipogenic activity, food intake and daily energy expenditure, and were, in fact, most pronounced in HF/FO mice. The effects of dietary PUFA replacement in an HF diet on expansion of adipose tissue might allow the favorable effects of dietary PUFA on dyslipidemia and hepatic steatosis. In light of other disadvantageous effects of weight gain, this might be a risky trade-off.

The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat

“…Differences in energy expenditure between vehicle-treated rats and rats treated with rimonabant were significant on the first day of the study, but not at later times (Herling et al 2008). A similar effect of rimonabant on energy expenditure had been reported previously in rats (Kunz et al 2008) yet in another study this CB 1 receptor antagonist/inverse agonist had no effect on energy expenditure in mice (Koolman et al 2010). These studies highlight the controversy (Vickers et al 2003; Thornton-Jones et al 2006; Janiak et al 2007; Kunz et al 2008)surrounding the proposed role of energy expenditure in weight changed induced by changes in CB 1 receptor activity (Ravinet Trillou et al 2003; Bensaid et al 2003; Jbilo et al 2005; Liu et al 2005; Osei-Hyiaman et al 2005; Horvath 2006; Cota 2007; Herling et al 2008; Nogueiras et al 2009; Cota et al 2009).…”

“…Treatment of rodents with a CB 1 antagonist/inverse agonist, such as rimonabant, causes reductions in daily food intake, but this effect is transient, and food intake soon returns to the level of vehicle-treated controls (Colombo et al 1998; Hildebrandt et al 2003; Vickers et al 2003; Ravinet Trillou et al 2003; Bensaid et al 2003; Liu et al 2005). This observation led to the hypothesis that the effect of CB 1 receptor antagonist/inverse agonists on body weight is maintained through actions on peripheral metabolic pathways (Ravinet Trillou et al 2003; Cota et al 2003; Jbilo et al 2005; Horvath 2006; Nogueiras et al 2008; Cota et al 2009; Koolman et al 2010). …”

A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease

“…Based on these properties, one may anticipate its pharmacodynamic activity on lipids specifically related to lipid disorders. [45] Picroside I has earlier been shown to be active in several models of liver toxicity. [43]…”

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…These evidence suggest that dietary PUFAs act on fat formation and thus on weight gain via the endocannabinoid system. This hypothesis has been reinforced by a study showing that blockade of CB1 receptor (with rimonabant) blocks weight gain induced by high fat diet [96]. However, evidence remains indirect and we can hardly conclude that the endocannabinoid system is the only pathway by which dietary PUFAs influence weight gain and adipose tissue formation.…”

“…It has been shown that a diet rich in ω-3 leads to weight loss, in parallel to a decrease of AEA and 2-AG [88,93]. Interestingly, a high fat diet rich in ω-3 does not induce weight gain, while a low fat diet rich in ω-6 increases weight gain [89,90,96]. These evidence suggest that dietary PUFAs act on fat formation and thus on weight gain via the endocannabinoid system.…”