Rimonabant is a selective cannabinoid CB₁ receptor antagonist that has undergone extensive testing in the treatment of obesity in human subjects. The story of rimonabant as an anti-obesity compound begins with the understanding that the endocannabinoid system (cannabinoid receptors and their endogenous ligands) plays a significant role in stimulating appetite through both central and peripheral mechanisms (see Di Marzo and Matias, 2005 for review). The rimonabant in obesity (RIO) program consisted of four phase III clinical trials (RIO-Europe, RIO-Lipids, RIO-North America and RIO-Diabetes) that compared rimonabant (5–20 mg per day) with placebo and showed that rimonabant reduced bodyweight and improved cardiovascular and metabolic risk factors in both non-diabetic overweight or obese patients and in overweight and obese subjects with type II diabetes, inadequately controlled by metformin or sulphonylureas (Scheen et al., 2006 for RIO-Diabetes results; Gadde and Allison, 2006 for review).

Obesity predisposes individuals to an increased risk of developing many diseases, including atherosclerosis, diabetes and some immune-mediated disorders. Importantly, obesity is associated with chronic inflammatory responses, such as arthritis and Crohn’s disease (Mokdad et al., 2003; Mehrotra et al., 2004), which are characterized by abnormal cytokine production, increased synthesis of C-reactive protein and the activation of pro-inflammatory signalling pathways (Wellen and Hotamisligil, 2005). Many of these inflammatory mediators are produced through a complex network involving both immune and metabolic systems. In fact, adipose tissue is no longer considered to be an inert tissue, but it is emerging as an important factor in the regulation of many pathological processes. Various products of adipose tissue have been described and, among these, certain cytokines mainly produced by the adipocytes have been named adipocytokines, particularly adiponectin and leptin. Other products of adipocytes include tumor necrosis factor- (TNF), interleukin-6, interleukin-1, mediators of the clotting process and certain complement factors (Wellen and Hotamisligil, 2005). The adipose tissue of obese individuals also contains a large number of macrophages, recruited by a chemokine released by adipocytes (CCL2), which are an additional source of cytokines (especially TNF) in the adipose tissue.

Adiponectin, exclusively produced by adipocytes, regulates the expression of many pro- and anti-inflammatory cytokines. Its main anti-inflammatory effect might be related to its capability to suppress the synthesis of TNF and interferon-, and to induce the production of anti-inflammatory mediators such as interleukin-10. Consequently, many diseases have been associated with a reduced level of adiponectin, including inflammatory bowel disease and rheumatoid arthritis. The role of leptin in regulating inflammatory responses is incompletely understood even though there is an increased expression of leptin in conditions associated with the release of pro-inflammatory cytokines, particularly in animal models of experimental autoimmune encephalomyelitis, antigen-induced arthritis or experimentally induced colitis. Its role as pro-inflammatory molecule in addition to regulating neuroendocrine function, energy homeostasis, haematopoiesis and angiogenesis, has become increasingly evident and has been recently reviewed (La Cava and Matarese, 2004). Together, these findings suggest that there are important pathways that link metabolism with the immune system and vice versa.

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