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Play an ADAGIO with a STRADIVARIUS: the right patient for CB1 receptor antagonists?

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 610–612 (2008)Cite this article

Accumulation of large quantities of intra-abdominal visceral fat usually accompanies overt obesity (BMI ≥30 kg/m2), but is also found in overweight individuals (BMI 25–29.9 kg/m2). Visceral or intra-abdominal adiposity is increasingly recognized as one of the major risk factors for type 2 diabetes, atherosclerotic plaque formation, and associated cardiovascular events.1 A strong phenotypic association exists between abdominal obesity—which can be easily assessed in clinical practice by measurements of waist circumference or waist-to-hip ratio—and two other major cardiovascular risk factors: high triacylglycerol and low HDL-cholesterol levels.1 Accumulation of visceral fat is accompanied by chronic inflammation, which can trigger atherosclerosis and insulin resistance. In abdominally obese individuals, these events are partly caused by low levels of adipocyte-derived adiponectin, which has a key role in insulin sensitization of the skeletal muscle.2,3 Adiponectin also counteracts the release of inflammatory cytokines from adipose tissue and thus decreases their inhibitory effects on insulin sensitivity and free fatty acid oxidation.2,3 These cytokines, in turn, contribute to atherosclerosis via enhanced endothelial cell activation, transendothelial migration of monocytes and endothelial adhesion of monocytes and neutrophils. Inflammatory cytokines also decrease the capability of adipocytes to store triacylglycerols,4 which leads to hypertriglyceridemia and ectopic fat formation in the liver, as well as to dyslipoproteinemia.

Evidence is accumulating that dysregulation of the endocannabinoid system has a role in the development of intra-abdominal obesity and subsequent lipotoxicity. In healthy adipocytes, endocannabinoids act at cannabinoid CB1 receptors to induce fatty-acid synthesis and triacylglycerol accumulation in several different ways, and are under negative-feedback control of insulin, leptin, and peroxisome proliferator-activated receptor γ.5 In obese rodents and humans, however, the endocannabinoid system becomes more active in visceral adipose depots and less active in peripheral subcutaneous adipose depots, which possibly contributes to the eventual accumulation of intra-abdominal fat at the expense of 'healthier' subcutaneous fat.5,6,7 Furthermore, activation of CB1 receptors in mature adipocytes decreases adiponectin expression.6 High plasma levels of endocannabinoid 2-arachidonoylglycerol in obese patients are less strongly associated with high BMI than with increased intra-abdominal obesity, high triacylglycerol levels, low HDL cholesterol, and insulin resistance.8,9 The pathologic role of increased CB1 receptor activation in the visceral adipose tissue of patients with intra-abdominal obesity is suggested by the observation that chronic administration of a CB1 receptor antagonist or inverse agonist to rodents and obese individuals reduces body weight independently of these agents' anorectic effects, and significantly ameliorates the altered metabolic and lipoprotein profiles that accompany obesity.5,10 One such compound, rimonabant, was developed by Sanofi-Aventis. After having completed four phase III studies—the Rimonabant In Obesity (RIO) trials11—this agent is currently marketed in more than 50 countries, as an adjunct to increased physical activity and exercise, to aid weight reduction in obese or overweight individuals with metabolic complications such as type 2 diabetes and dyslipidemia.

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  1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli (NA), Italy vdimarzo@icmib.na.cnr.it

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  1. V Di Marzo is Research Director at the Italian National Research Council, Pozzuoli, Naples, Italy, and Coordinator of the Endocannabinoid Research Group in Naples.,

    Vincenzo Di Marzo

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V Di Marzo has received research support and Speakers' Bureau honoraria from Sanofi-Aventis.

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Di Marzo, V. Play an ADAGIO with a STRADIVARIUS: the right patient for CB1 receptor antagonists?. Nat Rev Cardiol 5, 610–612 (2008). https://doi.org/10.1038/ncpcardio1319

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