Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112: 423-431

University of Milan, Milano, Lombardy, Italy
Journal of Clinical Investigation (Impact Factor: 13.22). 08/2003; 112(3). DOI: 10.1172/JCI200317725
Source: OAI


The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1(+/+)) littermates, mice lacking CB 1 (CB1(-/-)) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1(-/-) mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1(-/-) mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity body temperature, or energy expenditure. Hypothalamic CB 1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and prepro-orexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1(-/-) mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced hpogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.

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    • "We used adult (8 weeks) male CB1-KO mice (Cota et al., 2003; Ravinet Trillou et al., 2004) and CaMK-CB1-KO mice and their wildtype (WT) littermates. In CaMK-CB1-KO mice, the CB1 receptor was deleted in forebrain neurons expressing the Ca2+/ calmodulin dependent kinase IIa, while CB1 expression is maintained in cortical GABAergic interneurons and in cerebellar neurons (Marsicano et al., 2003). "
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    ABSTRACT: Cumulative data indicate that the endocannabinoid system plays a major role in feeding behaviour and energy balance. Genetic silencing of cannabinoid receptor type 1 (CB1) reduces body weight gain, independently of food intake. In this work, we investigated whether hypothalamic neuropeptide expression pattern supports the absence of anorexigenic response observed under constitutive CB1 ablation, by using neuronal CB1 conditional null mice (CamK-CB1-KO) and whole body CB1 null mice (CB1-KO). Our data showed that both CB1 null models display a marked decrease in proopiomelanocortin (POMC) and CART expression in the arcuate nucleus of the hypothalamus (ARC). This evidence suggests that lack of hypophagia is associated with the suppression of ARC anorexigenic neuropeptides and that behavioral changes in food intake (or lack thereof) after constitutive CB1 ablation are likely mediated by impaired melanocortin and CART signaling in the hypothalamus. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 02/2015; 18(9). DOI:10.1093/ijnp/pyv011 · 4.01 Impact Factor
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    • "When suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, leptin fails to exert some of its actions on lipid metabolism in WAT (Buettner et al., 2008). Additionally, CB1 receptor knockout mice have significantly less fat mass and a lower caloric intake than wild-type animals and are resistant to diet induced obesity (Cota et al., 2003). "
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    ABSTRACT: The G protein-coupled receptor GPR55 has been proposed as a new cannabinoid receptor associated with obesity in humans. We have investigated the regulation of GPR55 in rat white adipose tissue (WAT) in different physiological and pathophysiological settings involved in energy balance. We compared GPR55 expression with Cannabinoid Receptor type 1 (CB1), which mediates the metabolic actions of endocannabinoids, by real time PCR and western blotting. Circulating levels of lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, were measured by liquid chromatography-mass spectrometry. Both WAT CB1 and GPR55 levels were increased after fasting and recovered after leptin treatment. Their expression was decreased during gestation and increased throughout lifespan. Orchidectomy diminished WAT CB1 and GPR55 expression whereas ovariectomized rats showed increased GPR55 but decreased CB1 levels. Alterations in pituitary functions also modified WAT CB1 and GPR55 levels. Serum LPI levels were inversely regulated by fasting and gonadectomy in comparison to WAT GPR55. Our findings indicate that GPR55 and LPI are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in energy status.
    Molecular and Cellular Endocrinology 12/2013; 383(1-2):159-169. DOI:10.1016/j.mce.2013.12.011 · 4.41 Impact Factor
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    • "various immunomodulatory effects, while CB1 receptors are primarily distributed in the central nervous system. However, recent studies have also demonstrated CB1 receptors in various peripheral tissues (e.g., myocardium) (Bonz et al., 2003; Batkai et al., 2004; Mukhopadhyay et al., 2007) human coronary artery endothelial and smooth muscle cells (Rajesh et al., 2007; Rajesh et al., 2008) adipose tissue (Cota et al., 2003; Engeli et al., 2005) and the liver (Engeli et al.,2005; Osei- Hyiaman et al., 2005; Mallat and Lotersztajn, 2008). "
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    ABSTRACT: Emerging evidence that the cannabinoid type 1 receptor (CB1) and its endogenous ligands, endocannabinoids, involved in regulation of feeding behavior and body weight. Over-activation of ECS is associated with metabolic diseases as dyslipidemia and insulin resistance involved in CAD and diabetes. The aim was to determine whether G1359A polymorphism of CNR1 associated with CAD with and without T2DM, and with T2DM patients free of CAD and elucidate the association of CNR1 polymorphism with CAD risk factors. The study was carried on 50 patients with CAD (25 patients with and 25 patients without T2DM), 25 patients with T2DM free of CAD and a group of 20 healthy subjects as a control group. Coronary artery angiography for patient group, serum lipid profile (TG, TC, LDL and HDL) and assessment of G1359A polymorphism of CNR1 by RFLP method were done. CAD patients with and without T2DM had significantly higher age, fasting blood glucose, systolic and diastolic blood pressure, male gender, smoking, and body mass index (BMI) compared with control. GG genotype and G allele of G1359A polymorphism were significantly associated with CAD patients with T2DM (p<0.05). G allele increased risk of occurrence of CAD with diabetes by 5.22 (OR) 95% CI (1.32-20.54). GG genotype was significantly associated with higher TC (p<0.01), LDLc (p<0.001) and BMI (p=0.001). Association of G1359A polymorphism with BMI and disordered lipid may explain in part its association with CAD patients with T2DM and may encourage use of cannabinoid receptor antagonist in treatment of these disorders. Copyright © 2013 Safaa I. Tayel, et al., This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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