Endocannabinoids (ECs) acting via CB1 receptors (CB1R) play an important role in the control of body weight and energy homeostasis. In clinical trials, the CB1R blocking drug rimonabant had been found effective in reducing body weight and improving cardiometabolic abnormalities in patients with the metabolic syndrome, but was withdrawn from the market in 2008 due to neuropsychiatric side effects. Several studies, including our own, indicate that CB1R in peripheral tissues contribute to the metabolic benefit of CB1R blockade (JCI 115:1298, 2005;JCI 118:3160-9, 2008), raising the possibility that peripheral CB1R may be selectively targeted in the treatment of the metabolic syndrome in order to minimize neuropsychiatric side effects. in 2010, we published the first evidence in support of the validity of this approach, using a novel, peripherally restricted CB1R antagonist, AM6545 (JCI 120:2953-66, 2010). AM6545 was equieffective with rimonabant in reversing steatosis and dyspidemias, but was less effective than rimonabant in reducing food intake, body weight and adiposity, as well as insulin and leptin resistance. The greater efficacy of rimonabant could be due to its blockade of CB1R in the brain or to its inverse agonist properties. To distinguish between these two possibilities, we have tested a novel, peripherally restricted CB1R inverse agonist, JD5037, developed at Jenrin Discoveries Inc. JD5037 is a highly potent (Kd: 0.3 nM) peripherally restricted CB1R antagonist with no central CB1R occupancy, documented by CB1R PET, at therapeutically effective doses. JD5037 is devoid of CB1R-mediated behavioral effects, but is fully equieffective with its brain-penetrant parent in reducing food intake, body weight, steatosis, insulin and leptin resistance and dyslipidemia. In leptin-deficient ob/ob mice, JD5037 is simlarly effective in reversiong steatosis and insulin resistance, but fails to affect food intake and body weight, suggesting the role of endogenous leptin in these latter effects. Indeed, JD5037 treatment of DIO mice reverses their leptin resistance by rapidly reversing their hyperleptinemia, through decreasing leptin expression and secretion by adipocytes and increasing megalin-mediated leptin clearance via the kidney. These findings indicate that targeting peripheral CB1R by inverse agonists has great promise in the treatment of obesity and its cardiometabolic complications. This study has now bee published in Cell Metabolism (2012). In followup studies we are analyzing the pharmacokinetics of JD5037 in collaboration with Dr. Noel Whittaker at the NIDDK Mass Spectrometry Core. We have previously shown that hepatic CB1R are necessary for diet-induced steatosis, insulin and leptin resistance to develop in mice (JCI 2008). To address the question whether activation of hepatic CB1R is sufficient for these effect, we have developed a rescue model, transgenic mice that express CB1R only in hepatocytes and analyzed glycemic control using a hyperinsulinemic clamp. High fat diet induces hepatic insulin resistance in wild-type mice but not in mice with global or hepatocyte-specific knockout of CB1R. CB1R-/- mice with transgenic re-expression of CB1R in liver are hyperinsulinemic as a result of reduced insulin clearance due to downregulation of the insulin degrading enzyme, yet have increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance. In mice with CB1R present in hepatocytes, high fat diet or CB1R activation results in ER stress, via activation of the Bip/PERK/eIF2alpha protein translation pathway. In human and murine isolated hepatocytes, CB1R activation causes ER-stres-dependent suppression phosphorylation of akt-2 by insulin, through stimulation of the serine/threomnine phosphatase Phlpp1. In human liver, CB1R expression is upregulated in non-salcoholic fatty liver disease. In conclusion, endocannabinoids contribute to diet-induced insulin resistance via hepatic CB1-mediated inhibition of insulin signaling and clearance. These findings have been published in Gastroenterology (2012). The results of a study we published last year in PNAS indicated that activation of hepatic CB1R by endogenous anandamide plays a key role in the early proliferative stage of liver regeneration, as observed following 2/3 partial hepatectomy (PHX). We further found that hepatic CB1R activation targets the expression key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator, forkhead box protein M1 (FoxM1). As some of these factors, such as FoxM1, has also been implicated in hepatocellular carcinoma, we are currently testing the role of the hepatic CB1R/anandamide system in the develpment and progression of chemically induced liver cancer in mice. Preliminary findings suggest the involvement of CB1R in the progression of this type of liver cancer.
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