Bronander and Bloch metabolic syndrome (MetSyn) (Alberti 1998; Expert Panel 2001). While considerable debate has developed surrounding the exact deﬁnition and utility of MetSyn, it appears clear that these risk factors do indeed cluster in patients who are overweight and/or exhibit signiﬁcant insulin resistance, and that this clustering increases the risk of both CVD (Lakka et al 2002) and T2DM (Lorenzo et al 2003), often referred to as “cardiometabolic risk.” Despite increased physician and patient awareness, the prevalence of obesity, MetSyn, and T2DM are increasing in the United States (Ford et al 2004) and worldwide (WHO 2006b). While lifestyle modiﬁcation, including heart-healthy eating, caloric restriction, and increased physical exercise, remain key to stemming this epidemic of cardiometabolic risk, novel pharmacological options that affect weight, insulin resistance, and other cardiometabolic risk factors simultaneously could have considerable clinical potential. Unfortunately, our current guidelines tend to focus on treating individual risk factors, and most of our current pharmacologi- cal interventions do not simultaneously address the multiple risk factors associated with increased cardiometabolic risk. Concomitant with increased awareness of the importance of MetSyn, our understanding of the role the adipocyte plays in the development of T2DM and CVD has also evolved. Traditionally, adipocytes have been thought of as mere stor- age depots for energy; however, there is now an increased understanding that the abdominal adipocyte is a metabolically active endocrine and paracrine organ that plays an important role in mediating lipogenesis, glucose homeostasis, and inﬂammation, most likely through effects on the synthesis of leptin, adiponectin, free fatty acids, tumor necrosis factor alfa, and plasminogin activation inhibitor-1 (Kershaw and Flier 2004). Pharmacological interventions that could affect adipocyte function could have a potentially beneﬁcial role in the modiﬁcation of cardiometabolic risk. Role of the endocannabinoid system in cardiometabolic risk Over the last 15 years, there has been considerable research involving the endocannabinoid system (ECS), an endogenous physiological system important in the regulation of feeding behavior, lipid metabolism, and energy balance. The system is composed of two G-protein cannabinoid receptors (CB-1, CB-2) and their associated endogenous ligands (De Petrocel- lis et al 2004). Anandamide (ADA) and 2-arachidonylgycerol (2-AG) are the most studied of the endogenous ligands. In mammals, CB-1 are found in the central nervous system, gastrointestinal organs, and adipose tissue. CB-2 182 are found almost exclusively in peripheral immune cells and are not thought to be involved in energy homeostasis (Howlett et al 2002). In the central nervous system, the endocannabinoids (ADA and 2-AG) are produced on-demand (not stored in vesicles) from phospholipids or triglycerides on the post- synaptic membrane (Piomelli 2003). Once produced, these molecules are immediately released into the synapse where they are free to activate the pre-synaptic CB-1 receptor. Binding to the pre-synaptic CB-1 receptor then inhibits the release of other neurotransmitters stored there (Di et al 2003). This process, called retrograde signaling, appears to act as a modulatory feedback system controlling neurotransmitter release. After interacting with the CB-1 receptor these ligands are immediately degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (Cravatt et al 1996; Dinh et al 2002). In the brain, CB-1 are found primarily in the mesolimbic areas and the hypothalamus. Compared with lean control animals, in the obese mouse model, hypothalamic levels of both ADA and 2-AG were found to be higher (Di Marzo et al 2001). Interestingly, levels of these ECS ligands were signiﬁcantly reduced when overweight and normal animals were subsequently administered the beneﬁcial gut hormone leptin. In another experiment, levels of 2-AG and ADA were measured in the rat brain during fasting, feeding, and after satiation (Kirkham et al 2002). Levels of the endocan- nabinoids were very high in the mesolimbic area of the fasting animals but lower in the feeding animals, suggesting this area is involved in motivational behavior to ﬁnd and consume food. CB-1 receptors are also found in peripheral tissues includ- ing adipocytes, pancreas, gut, liver and muscle. Compared with lean controls, adipocytes from obese rats exhibited a greater than 3-fold upregulation in expression of CB-1, demonstrated by increased levels of messenger RNA (Bensaid et al 2003). Stimulation of CB-1 in adipose tissue induces li- poprotein lipase activity while blockade causes up-regulation of the protein adiponectin. Adiponectin increases free fatty acid oxidation and increased insulin sensitivity in skeletal muscle and liver, while decreasing vascular inﬂammation (Chandran et al 2003). In skeletal muscle, CB-1 stimulation reduces insulin-mediated glucose uptake (Liu et al 2005). In the liver, ECS activation leads to increases in de novo lipogenesis, a critical component in diet-induced obesity (Osei-Hyiaman et al 2005), and in the gastrointestinal tract, ADA levels increase during food deprivation suggesting a peripheral hunger signal (Gomez et al 2002). Vascular Health and Risk Management 2007:3(2)