Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of
coronary heart disease. First-line
therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic
therapy. One system that has gained recent attention is the
endocannabinoid system. The
endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced
obesity.
Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive
endocannabinoid system could have therapeutic benefit not only for
weight loss but also for the atherogenic
dyslipidemia and
insulin resistance that cluster with
abdominal obesity in particular. Animal models have been critical for elucidating the role of the
endocannabinoid system in
obesity and in demonstrating that antagonism with
rimonabant can induce loss of visceral fat and improve
insulin sensitivity. Early human trials with
rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic
dyslipidemia,
insulin resistance, and markers of
inflammation. Interestingly, some of these beneficial metabolic effects are partially
weight-loss-independent, confirming the importance of peripheral
endocannabinoid system effects in addition to central effects.