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Georg Kunos, National Institute of Health, USA;
Obesity and its metabolic complications are associated with increased activity of the endocannabinoid/CB1 receptor (CB1R) system, as indicated by the beneficial effects of CB1R antagonists. However, neuropsychiatric side effects halted the therapeutic development of this class of compounds. As these side effects are due to blockade of CB1R in the CNS, whereas blockade of CB1R in peripheral tissues contribute to metabolic improvements, limiting the brain penetrance of CB1R antagonists may be a way out of this conundrum. We have tested a novel, peripherally restricted CB1R inverse agonist, JD5037, in mice with diet-induced obesity/insulin resistance (DIO mice). Chronic treatment of DIO mice with JD5037 or its brain-penetrant parent compound SLV-319 was equieffective in reducing food intake and adiposity and reversing hepatic steatosis and insulin resistance. The JD5037-induced appetite and weight reduction, but not the improvements in steatosis or glycemic control, are due to resensitizing DIO mice to endogenous leptin. This is secondary to the rapid reversal of hyperleptinemia via inhibition of leptin production in adipocytes and facilitation of leptin clearance by the kidney. We next tested the effects of JD5037 in a rat model of overt T2DM. Young ZDF rats have compensated insulin resistance, which progresses to uncompensated hyperglycemia due to beta-cell failure. β-Cell failure in ZDF rats is associated with CB1R-activation of the Nlrp3-ASC inflammasome in M1 macrophages infiltrating pancreatic islets. These effects are replicated in vitro by incubating human or rodent macrophages but not macrophages from CB1R-/- or Nlrp3-/- mice with the endocannabinoid anandamide (AEA). Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R prevents these changes, and restores normoglycemia and glucose-induced insulin secretion. We conclude that in diet-induced obesity peripheral CB1R blockade not only improves cardiometabolic risk, but also has antiobesity effects by reversing leptin resistance. Peripheral CB1R blockade also has weight-independent beneficial effects in overt T2DM by preventing β-cell loss due CB1R-mediated inflammasome activation in macrophages that infiltrate the pancreatic islets. These findings highlight the therapeutic potential of peripheral CB1R blockade in both the metabolic syndrome and in overt T2DM. Supported by intramural NIH funds.