The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity, and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type-1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist, rimonabant, in high-fat diet (HFD)-induced obese adiponectin knockout mice and their wild-type littermate controls. HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol and triglyceride levels in the two strains. Rimonabant treatment reversed the hepatic steatosis and hepatocellular damage only in the wild-type mice, while it improved glucose homeostasis and insulin sensitivity to the same extent in both wild-type and adiponectin knockout mice. These findings are interpreted to indicate that CB1 blockade reverses the HFD-induced hepatic steatosis is mediated by adiponectin, whereas the parallel improvements in other metabolic parameters, including glycemic control and insulin sensitivity, develop independently of adiponectin. This study has been published in Amer J Physiol Endocr Metab 306:E457, 2014. T2DM progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. our findings reported last year (Nature Medicine 19:1132, 2013) implicate pro-inflammatory macrophages infiltrating pancreatic islets in a paracrine mechanism of beta cell loss, and identify macrophage-expressed CB1 receptors as a therapeutic target in T2DM. ZDF rats also display pronounced diabetic nephropathy, and we have explored the possible pathogenic role of the EC/CB1 receptor system. Diabetic nephropathy is a major cause of end-stage kidney disease, and over-activity of the endocannabinoid/cannabinoid 1 receptor (CB1R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type-2 diabetic nephropathy with albuminuria, glycosuria, reduced glomerular filtration, activation of the renin-angiotensin system (RAS), oxidative/nitrative stress, podocyte loss and increased CB1R expression in glomeruli. Peripheral CB1R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Clodronate-mediated macrophage depletion, which was earlier reported to prevent β-cell loss and hyperglycemia in ZDF rats, did not affect the development of nephropathy. On the other hand, treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and downregulated renal cortical CB1R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB1R and desmin gene expression were increased while podocin and nephrin content were decreased by either the CB1R agonist arachydonoyl-2-chloroethylamide, angiotensin II or high glucose, and the effects of all three were antagonized by CB1R blockade, siRNA-mediated knockdown of CNR1 or Agtr1 antagonism by losartan. We conclude that increased CB1R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB1R blockade. A manuscript summarizing these findings has been submitted for publication and is currently under review. Hepatocellular carcinoma (HCC), the most common form of liver cancer, has high mortality and no adequate treatment. Endocannabinoids are lipid mediators that interact with hepatic CB1 receptors (CB1R) to promote hepatocyte proliferation in the early stages of liver regeneration via inducing cell cycle proteins involved in mitotic progression, including FOXM1 (PNAS 108:6323, 2011). Because FOXM1 is also highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in mice with diethylnitrosamine (DEN)-induced HCC as well as in human HCC. Postnatal DEN-treatment induced HCC within 8 months in wild-type mice, with the size of tumors being significantly lower in CB1R-/- mice or in wild-type mice treated with the peripherally restricted CB1R antagonist JD5037. Tumor-induced, CB1R-mediated changes in hepatic gene expression were identified by transcriptome analysis of normal and cancerous tissue from individuals with HCC and from wild-type and CB1R-/- mice, and further confirmed by real-time PCR and functional assays. The hepatic expression of CB1R and its endogenous ligand anandamide is increased in both human and murine HCC. Among the genes prominently induced in HCC in a CB1R-dependent manner are FOXM1 and a number of its downstream targets, including the tryptophan catalyzing enzyme indoleamine 2,3-dioxygenase (IDO2). The observed increased expression and activity of IDO2 in cancerous versus normal liver tissue and the consequent induction of immunosuppressive Treg cells and upregulation of tumor-related angiogenesis contribute to immune tolerance to the tumor. All these changes were attenuated by pharmacological inhibition or genetic ablation of CB1R, which points to the therapeutic potential of peripheral CB1R blockade in the treatment of HCC. A manuscript summarizing these findings has been submitted for publication and is currently under review. During this review period we have developed novel, dual-target compounds for the treatment of various pathologies associated with fibrosis. These compounds are non brain-penetrant CB1 receptor antagonists and also act as inhibitors of inducible NO synthase (iNOS). In several rodent models of liver fibrosis, the dual inhibitors had superior antifibrotic activity compared to single target CB1 receptor antagonists. A patent application has been filed (PCT/US2013/069686).
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