Hepatic targeting of the centrally active cannabinoid 1 receptor (CBR) blocker rimonabant via PLGA nanoparticles for treating fatty liver disease and diabetes.

Over-activation of the endocannabinoid/CBR system is a hallmark feature of obesity and its related comorbidities, most notably type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Although the use of drugs that widely block the CBR was found to be highly effective in treating all metabolic abnormalities associated with obesity, they are no longer considered a valid therapeutic option due to their adverse neuropsychiatric side effects. Here, we describe a novel nanotechnology-based drug delivery system for repurposing the abandoned first-in-class global CBR antagonist, rimonabant, by encapsulating it in polymeric nanoparticles (NPs) for effective hepatic targeting of CBRs, enabling effective treatment of NAFLD and T2D.

Herbal Cannabis Use Is Not Associated with Changes in Levels of Endocannabinoids and Metabolic Profile Alterations among Older Adults.

Activation of the endocannabinoid system has various cardiovascular and metabolic expressions, including increased lipogenesis, decreased blood pressure, increased heart rate, and changes in cholesterol levels. There is a scarcity of data on the metabolic effects of exogenous cannabis in older adults; therefore, we aimed to assess the effect of exogenous cannabis on endocannabinoid levels and the association with changes in 24 h ambulatory blood pressure and lipid levels. We conducted a prospective study of patients aged 60 years or more with hypertension treated with a new prescription of herbal cannabis.

The Metabolic Efficacy of a Cannabidiolic Acid (CBDA) Derivative in Treating Diet- and Genetic-Induced Obesity.

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader-Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD).

Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption.

Background: Inflammatory bowel diseases (IBDs) are chronic, idiopathic, inflammatory, gastrointestinal disorders. The endocannabinoid system may have a role in the pathogenesis of IBD. We aimed to assess whether cannabis treatment influences endocannabinoids (eCBs) level and clinical symptoms of IBD patients.

Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight Loss.

Bariatric operations induce weight loss, which is associated with an improvement in hepatic steatosis and a reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet and compared them to diet and weight-matched sham-operated mice (WMS).

CBR regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance.

The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CBR system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CBR modulates sOb-R levels and hepatic leptin resistance.

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent.

Objective: The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CBR), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown.

Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans.

Background: The endocannabinoid (eCB) system plays a key role in the development of obesity and its comorbidities. Limited information exists on the changes in circulating eCBs following bariatric surgery.

Objectives: This study aims to (i) assess the circulating levels of eCBs and related molecules and (ii) examine the association between their levels and numerous clinical/metabolic features pre- and post-operatively.

The therapeutic potential of targeting the peripheral endocannabinoid/CB receptor system.

Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CBR and CBR, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CBR system in modulating the metabolism in several peripheral organs.

Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease.

Objective: To evaluate the association between circulating levels of endocannabinoids (eCBs) and non-alcoholic fatty liver disease (NAFLD).

Methods: The serum levels of the main eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed by liquid chromatography/tandem mass spectrometry in 105 volunteers screened for NAFLD. Hepatic ultrasound, fasting blood tests, and anthropometrics were assessed.

Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells.

Constitutive expression of active Akt (Akttg) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6), an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6P-/-). rpS6 phosphorylation deficiency failed to block Akttg-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation.