26 AEA showed a similar effect, although the eventual cell death was by necrosis rather than apoptosis.59 For both endocannabinoids, these effects occur in the 2 to 50 μM range. The hepatic concentration of AEA is orders of magnitude below such levels, whereas 2-AG may reach low micromolar concentrations.26 Because the proapoptotic effect of 2-AG is independent of CB receptors, it could contribute to the reduction of fibrotic activity observed after CB1 blockade.48 The profibrotic and

adverse hemodynamic effects of CB1 activation could provide a rationale for the use of CB1 antagonists in the medical management of advanced liver cirrhosis. The CB1-mediated, appetite-promoting effect of endocannabinoids60 was the primary impetus for the development Selleckchem Smoothened Agonist of brain-penetrating CB1 receptor antagonists for the treatment of obesity. The first-in-class compound rimonabant caused weight reduction and improved the associated cardiometabolic risk factors, but neuropsychiatric side effects, including depression and anxiety, have prevented its approval in the United States and have led to its withdrawal from the market in other countries (reviewed by Rosenson61). Accumulating evidence indicates,

however, that the metabolic effects of endocannabinoids are mediated, at least in part, by peripheral CB1 receptors, as discussed in some detail later.

Indeed, a non–brain-penetrating MCE CB1 antagonist was recently reported to retain the beneficial metabolic effects of rimonabant in obese mice without producing the Selleck Pexidartinib behavioral effects that predict neuropsychiatric side effects in humans; this may revive interest in the therapeutic potential of CB1 antagonism.62 Reduced food intake is not the primary mechanism of weight reduction by CB1 blockade in obesity. In mice with diet-induced obesity (DIO), chronic use of rimonabant caused a transient reduction in food intake and sustained weight loss, and this indicated food intake–independent effects on energy balance.2, 63 Increased de novo hepatic lipogenesis has been documented in DIO mice2, 64, 65 and in people with NAFLD66, 67 and may be mediated by endocannabinoids. Indeed, lipogenic gene expression and the rate of de novo hepatic lipogenesis were increased by CB1 agonists and decreased by CB1 antagonists in rodents.2, 4, 25, 68, 69 A high-fat diet increases hepatic CB1 expression2, 4, 21, 25 and the hepatic levels of AEA.2 Thus, endogenous AEA acting via hepatic CB1 receptors contributes to increased de novo lipogenesis in mouse models of obesity. CB1-mediated hepatic lipogenesis may explain the finding that in patients with chronic hepatitis C infection, daily cannabis smoking was an independent risk factor for steatosis severity but not for obesity.