jd5037 and Body-Weight

In visceral obesity, an overactive endocannabinoid/CB. We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.. Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY. Peripheral CB

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cannabinoids; Diet, High-Fat; Dietary Fats; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Melanocortin, Type 4; Receptors, Cannabinoid; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sulfonamides

Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB. We studied eCB 'tone' in individuals with PWS and in the. Dysregulation of the eCB/CB

Topics: Adult; Animals; Antigens, Neoplasm; Arachidonic Acids; Body Weight; Case-Control Studies; Disease Models, Animal; Endocannabinoids; Female; Glycerides; Humans; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Prader-Willi Syndrome; Proteins; Pyrazoles; Receptor, Cannabinoid, CB1; Sulfonamides; Weight Loss

Obesity is associated with increased activity of two lipid signaling systems (endocannabinoids [ECs] and ceramides), with both being implicated in insulin resistance. Cannabinoid-1 receptor (CB1 R) antagonists reverse obesity and insulin resistance, but have psychiatric side effects. Here we analyzed the role of ceramide in CB1 R-mediated insulin resistance in C57Bl6/J mice with high-fat diet-induced obesity (DIO), using JD5037, a peripherally restricted CB1 R inverse agonist. Chronic JD5037 treatment of DIO mice reduced body weight and steatosis and improved glucose tolerance and insulin sensitivity. Peripheral CB1 R blockade also attenuated the diet-induced increase in C14:0, C16:0, C18:0, and C20:0 ceramide species with either C16 or C18 sphingosine-base in the liver. Decreased ceramide levels reflected their reduced de novo synthesis, due to inhibition of the activity of serine-palmitoyl transferase (SPT) and the expression of its SPTLC3 catalytic subunit, as well as reduced ceramide synthase (CerS) activity related to reduced expression of CerS1 and CerS6. JD5037 treatment also increased ceramide degradation due to increased expression of ceramidases. In primary cultured mouse hepatocytes and HepG2 cells, the EC anandamide increased ceramide synthesis in an eIF2α-dependent manner, and inhibited insulin-induced akt phosphorylation by increased serine phosphorylation of IRS1 and increased expression of the serine/threonine phosphatase Phlpp1. These effects were abrogated by JD5037 or the SPT inhibitor myriocin. Chronic treatment of DIO mice with myriocin or JD5037 similarly reversed hepatic insulin resistance, as verified using a euglycemic/hyperinsulinemic clamp.. ECs induce CB1 R-mediated, endoplasmic reticulum stress-dependent synthesis of specific ceramide subspecies in the liver, which plays a key role in obesity-related hepatic insulin resistance.

Topics: Animals; Body Weight; Ceramides; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Liver; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; Liver; Mice; Mice, Inbred C57BL; Obesity; Pyrazoles; Receptor, Cannabinoid, CB1; Serine C-Palmitoyltransferase; Sulfonamides; Up-Regulation

Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.

Topics: Adipocytes; Animals; Anti-Obesity Agents; Body Weight; Drug Inverse Agonism; Drug Resistance; Fatty Liver; Insulin Resistance; Leptin; Mice; Molecular Structure; Obesity; Pyrazoles; Receptor, Cannabinoid, CB1; Regression Analysis; Sulfonamides