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

International Journal of Obesity volume 34, pages 374–384 (2010)Cite this article

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 CB1-receptor antagonist (rimonabant).

Methods:

Mice were treated with rimonabant (10 mg kg−1 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 poly-unsaturated 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.

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Acknowledgements

We thank Solvay for providing rimonabant. This study was financially supported by a grant from Kruidvat and UMCG to the Groningen Expert Centre on Childhood Obesity (to PJJS) and from the Dutch Diabetes Foundation (to GvD). We thank Mark Doornbos for technical assistance.

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Authors and Affiliations

  1. Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    A H Koolman, V W Bloks, M H Oosterveer, F Kuipers & P J J Sauer

  2. Unit Neuroendocrinology, Center for Behavioral Neurosciences, University of Groningen, Haren, The Netherlands

    I Jonas & G van Dijk

  3. Center for Isotope Research, University of Groningen, Groningen, The Netherlands

    G van Dijk

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  1. A H Koolman
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Correspondence to G van Dijk.

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Koolman, A., Bloks, V., Oosterveer, M. et al. Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition. Int J Obes 34, 374–384 (2010). https://doi.org/10.1038/ijo.2009.219

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