piperidines and Fatty-Liver

The endocannabinoid system comprises receptors, CB1 and CB2, their endogenous lipidic ligands and machinery dedicated to endocannabinoid synthesis and degradation. An overactive endocannabinoid system appears to contribute to the pathogenesis of several diseases, including liver diseases. With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic, the development of effective therapies is gaining considerable interest. Several recent experimental lines of evidence identify CB receptors as potential novel therapeutic targets in the management of NAFLD. Endogenous activation of peripheral CB1 receptors is a key mediator of insulin resistance and enhances liver lipogenesis in experimental models of NAFLD. Moreover, we have shown that adipose tissue CB2 receptors are markedly upregulated and promote fat inflammation, thereby contributing to insulin resistance and liver steatosis. Data from our group also indicate that tonic activation of CB1 receptors is responsible for progression of liver fibrosis, whereas CB2 receptors display anti-fibrogenic properties. The clinical relevance of these findings is supported by studies in patients with chronic hepatitis C indicating that daily cannabis use is an independent predictor of both fibrosis and steatosis severity. Moreover, preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat. Tempering these promises, the first generation of CB1 antagonists raised concern due to an alarming rate of mood disorders and the development program of these molecules was suspended. Current research efforts are therefore focused on developing formulations of CB1 antagonists that do not enter the central nervous system, and preliminary experimental data obtained with such molecules are encouraging.

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Liver; Humans; Hypertension, Portal; Inflammation; Insulin Resistance; Liver Cirrhosis; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies.. All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved. Relative risks (RR) with 95% confidence interval for relevant adverse events and number needed to harm was calculated.. Nine trials (n = 9635) were considered. Rimonabant 20 mg was associated with an increased risk of adverse event (RR 1.35; 95%CI 1.17-1.56), increased discontinuation rate (RR 1.79; 95%CI 1.35-2.38), psychiatric (RR 2.35; 95%CI 1.66-3.34), and nervous system adverse events (RR 2.35; 95%CI 1.49-3.70). The number needed to harm for psychiatric adverse events is 30.. Rimonabant is associated with an increased risk of adverse events. Despite of an increasing interest for its use on fatty liver, the security profile and efficacy it is needs to be carefully assessed before its recommendation. At present the use of rimonabant on fatty liver cannot be recommended.

Topics: Cannabinoid Receptor Antagonists; Fatty Liver; Humans; Mental Disorders; Nervous System Diseases; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Treatment Outcome

The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.

Topics: Animals; Antioxidants; Bariatric Surgery; Body Mass Index; Cannabinoids; Cholagogues and Choleretics; Comorbidity; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Lactones; Life Style; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Treatment Outcome; Ursodeoxycholic Acid; Weight Loss

Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis.. To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23).. Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups.. We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

Topics: Adult; Aged; Cannabinoid Receptor Antagonists; Double-Blind Method; Fatty Liver; Female; Finland; Humans; Liver; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Treatment Outcome; Weight Loss

Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4

Topics: Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Drug Design; Fatty Liver; Male; Mice; Piperidines; Rats; Retinol-Binding Proteins, Plasma; Tissue Distribution

Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (

Topics: Animals; Cannabinoid Receptor Antagonists; Cytochrome P-450 Enzyme System; Dogs; Drug Inverse Agonism; Fatty Liver; Female; Humans; Liver; Madin Darby Canine Kidney Cells; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Piperidines; Purines; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling.. Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism.. Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance.. These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting "cross-talk" between liver and adipose tissue sphingolipids.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Ceramidases; Fatty Liver; Glucose; Hepatocytes; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Liver; Mice; Mice, Transgenic; Piperidines; Receptors, Adiponectin

KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) has been reported to cause hepatic fat loss. However, the action mechanisms of KMUP-1 in obesity-induced steatohepatitis remains unclear. This study elucidated the steatohepatitis via matrix metallopeptidase 9 (MMP-9) and tumor necrosis factor α (TNFα), and related lipolysis via hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) by KMUP-1. KMUP-1 on steatohepatitis-associated HSL/p-HSL/ATGL/MMP-9/TNFα/interleukin-10 (IL-10) and infiltration of M1/M2 macrophages in obese mice were examined. KMUP-1 was administered by oral gavage from weeks 1-14 in high-fat diet (HFD)-supplemented C57BL/6J male mice (protection group) and from weeks 8-14, for 6 weeks, in HFD-induced obese mice (treatment group). Immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining of tissues, oil globules number and size, infiltration and switching of M1/M2 macrophages were measured to determine the effects on livers. IL-10 and MMP-9 proteins were explored to determine the effects of KMUP-1 on M1/M2 macrophage polarization in HFD-induced steatohepatitis. Long-term administration of KMUP-1 reversed HFD-fed mice increased in body weight, sGOT/sGPT, triglyceride (TG) and glucose. Additionally, KMUP-1 decreased MMP-9 and reactive oxygen species (ROS), and increased HSL/p-HSL and IL-10 in HFD mice livers. In conclusion, KMUP-1, a phosphodiesterase inhibitor (PDEI), was shown to reduce lipid accumulation in liver tissues, suggesting that it could be able to prevent or treat steatohepatitis induced by HFD.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Fatty Liver; Interleukin-10; Liver; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Obese; Piperidines; Reactive Oxygen Species; Sterol Esterase; Theophylline; Triglycerides; Tumor Necrosis Factor-alpha; Xanthines

The present study investigated the comparative effects of piperine (PIP) - the active ingredient of black and long peppers - and simvastatin (SIM) on hepatic steatosis in hyperlipidemic rats. Male Wistar rats were fed a cholesterol mixture daily by intragastric gavage for 8 weeks. Piperine was given by oral gavage 8 h after cholesterol feeding. The animals were divided into 4 groups: control, high fat (HF), high fat plus 40 mg PIP/kg, and high fat plus 2 mg SIM/kg. At the end of the treatment, liver cholesterol, triglyceride, thiobaribituric reacting substances, superoxide dismutase (SOD), serum aminotransferase (AST), and alanine transferase (ALT) were measured. The result demonstrated that PIP and SIM significantly reduced the accumulation of cholesterol, triglyceride, and lipid peroxidation in the liver, while elevation of SOD was observed. The activities of AST and ALT significantly decreased in PIP when compared with the HF group. Our in vitro study of pancreatic lipase also showed the inhibitory effect of PIP higher than 30% at 5 mmol/L. These results demonstrate that PIP has beneficial effects in the treatment and (or) prevention of fat accumulation in the liver and that this mechanism is due to the inhibition of pancreatic lipase and the improvement of oxidative status.

Topics: Adipose Tissue; Alkaloids; Animals; Antioxidants; Benzodioxoles; Diet, High-Fat; Dietary Fats; Fatty Liver; Hyperlipidemias; Male; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Simvastatin

To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice.. The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined.. Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in β-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice.. BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eating; Energy Metabolism; Fatty Liver; Ion Channels; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis; Thiophenes; Uncoupling Protein 1; Weight Loss

Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.

Topics: Animals; Benzoxazines; Blotting, Western; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Liver; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, CCR2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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 (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). 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 improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.

Topics: Adiponectin; Adiposity; Animals; Body Weight; Cannabinoid Receptor Antagonists; Diet, High-Fat; Energy Intake; Fatty Liver; Leptin; Lipid Metabolism; Lipids; Liver; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.

Topics: Adiponectin; Adipose Tissue, Brown; alpha 1-Antitrypsin; AMP-Activated Protein Kinase Kinases; Animals; Diet, High-Fat; Energy Metabolism; Fatty Acids; Fatty Liver; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Ion Channels; Leptin; Leukocyte Elastase; Liver; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Obesity; Oxidation-Reduction; Phosphorylation; Piperidines; Protein Kinases; Uncoupling Protein 1; Weight Gain

Effects of cannabinoid receptor 1 (CB1R) blockade were observed by comparing 9-day and 6-week SR141716 treatments in monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity (HO) in rats for the first time and molecular mechanisms were investigated. Compared with normal rats, the MSG rats display typical symptoms of the metabolic syndrome, i.e., excessive abdominal obesity, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and hepatic steatosis, but with lower food intake. Although both the 9-day and 6-week treatments with the specific CB1R antagonist SR141716 effectively lowered body weight, intraperitoneal adipose tissue mass, serum triglyceride (TG), and insulin level, the effect of chronic treatment is more impressive. Moreover, serum cholesterol, free fatty acids (FFA), fasted and postprandial blood glucose, and insulin insensitivity were more effectively improved by 6-week exposure to SR141716, whereas hypophagia was only effective within the initial 2 weeks. In addition, hepatic steatosis as well as hepatic and adipocyte morphology was improved. Western blot analysis revealed that the markedly increased CB1R expression and decreased insulin receptor (INR) expression in liver and adipose tissues were effectively corrected by SR141716. Consistent with this, deregulated gene expression of lipogenesis and lipolysis as well as glucose metabolic key enzymes were also restored by SR141716. In conclusion, based on present data we found that: (1) alteration of the hypothalamus in MSG rats leads to a lower expression of INR in crucially insulin-targeted tissues and hyperinsulinemia that was reversed by SR141716, (2) the abnormally increased expression of CB1R in liver and adipose tissues plays a vital role in the pathophysiological process of MSG rats, and (3) chronic CB1R blockade leads to a sustained improvement of the metabolic dysfunctions of MSG rats.

Topics: Adipose Tissue; Animals; Animals, Newborn; Cannabinoid Receptor Antagonists; Fatty Liver; Female; Glucose Intolerance; Hyperlipidemias; Insulin Resistance; Liver; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Insulin; Rimonabant; Sodium Glutamate

Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under caloric restriction. In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by caloric restriction. The treatment increased fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti-obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti-obesity effect was accompanied by improvement in plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an adjunct to diet restriction or to an appetite suppressant for the treatment of obesity and related metabolic disorders.

Topics: Adiposity; Animals; Basal Metabolism; Bile Acids and Salts; Body Weight; Caloric Restriction; Diet; Drug Therapy, Combination; Fatty Acids; Fatty Liver; Feeding Behavior; Fibroblast Growth Factors; Gene Expression Regulation; Hepatocytes; Insulin; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligonucleotides, Antisense; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Fibroblast Growth Factor, Type 4; Rimonabant

Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome.. Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed.. Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers.. Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

Topics: Animals; Biomarkers; Cannabinoid Receptor Antagonists; Eating; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Weight Gain

This study examined the effect of piperine on hepatic steatosis and insulin resistance induced in mice by feeding a high-fat diet (HFD) for 13 weeks and elucidated potential underlying molecular mechanisms. Administration of piperine (50 mg/kg body weight) to mice with HFD-induced hepatic steatosis resulted in a significant increase in plasma adiponectin levels. Also, elevated plasma concentrations of insulin and glucose and hepatic lipid levels induced by feeding a HFD were reversed in mice when they were administered piperine. However, piperine did not reduce body weight and other biochemical markers to an extent where they became equal to the levels found in the CD-fed mice. Piperine reversed HFD-induced down-regulation of adiponecitn-AMP-activated protein kinase (AMPK) signalling molecules which play an important role in mediating lipogenesis, fatty acid oxidation and insulin signalling in the livers of mice. The expressions of lipogenic target genes were decreased, whereas the expression of carnitine palmitoyltransferase 1 (CPT1) gene involved in fatty acid oxidation was increased in the livers of the Pin50 group. Piperine significantly decreased the phosphorylation of insulin receptor substrate-1 (IRS-1) compared with the HFD-fed mice. Administration of piperine appeared to reverse preexisting HFD-induced hepatic steatosis and insulin resistance, probably by activation of adiponectin-AMPK signalling in mice.

Topics: Adiponectin; Alkaloids; AMP-Activated Protein Kinases; Animals; Benzodioxoles; Diet, High-Fat; Fatty Liver; Humans; Insulin Resistance; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Triglycerides

Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.

Topics: Alanine Transaminase; Animals; Disease Models, Animal; Enzyme Inhibitors; Fatty Liver; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Piperidines; Protective Agents; Pyridazines; Rats; Stearoyl-CoA Desaturase; Triglycerides

It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N-hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O(2) consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated ß-oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA-induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high-density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism.. These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Carbohydrate Metabolism; Cholesterol; Disease Models, Animal; Dyslipidemias; Fatty Liver; Gene Expression Regulation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Oxygen Consumption; Piperidines; Protein Kinases; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Tissue Culture Techniques

This study investigated the role of piperine in the transcriptional regulation of liver X receptor α (LXRα) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXRα activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRα and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXRα mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBPα, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2α, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXRα transcriptional activity by abolishing the interaction of ligand-bound LXRα with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXRα-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD.

Topics: Alkaloids; Animals; Base Sequence; Benzodioxoles; Blotting, Western; Dietary Fats; DNA Primers; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; HEK293 Cells; Humans; Insulin; Mice; Piperidines; Polymerase Chain Reaction; Polyunsaturated Alkamides; Signal Transduction

Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Alanine Transaminase; Animals; Barbiturates; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tissue Distribution; Triglycerides

Fat Aussie mice (foz/foz) are morbidly obese, glucose intolerant and have liver steatosis that develops into steatohepatitis on a high-fat diet. The cannabinoid 1 receptor (CB1) antagonist SR141716 has been shown to improve obesity-associated metabolic complications in humans and rodent models. The aim of this study was to assess the effect of SR141716 in foz/foz mice.. Male wildtype (WT) and foz/foz mice were fed a chow or high-fat diet (45% saturated fat). Vehicle or SR141716 (10 mg kg(-1) per day) was administered in jelly once daily for 4 weeks from 4 months of age.. Foz/foz mice were obese but had less epididymal adipose tissue mass than fat-fed WT mice despite being significantly heavier. Liver weight was increased by twofold in foz/foz compared with WT mice and showed significant steatogenesis associated with impaired liver function. Foz/foz and fat-fed WT mice were glucose intolerant as determined by oral glucose tolerance test. In chow-fed foz/foz mice, SR141716 reduced body weight, liver weight, reversed hepatosteatosis and glucose intolerance. Subcutaneous white adipose tissue gene expression of the macrophage-specific marker Cd68 reflected the improvements in the metabolic status by SR141716 in these mice.. The results are consistent with the hypothesis that foz/foz mice have defective lipid metabolism, are unable to adequately store fat in adipose tissue but instead sequester fat ectopically in other metabolic tissues (liver) leading to insulin resistance and hepatic steatosis associated with inflammation. Our findings suggest that SR141716 can improve liver lipid metabolism in foz/foz mice in line with improved insulin sensitivity and adipose tissue inflammation.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Adult; Biomarkers; Cannabinoid Receptor Modulators; Cholesterol; Fatty Liver; Female; Humans; Hypercholesterolemia; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Safety-Based Drug Withdrawals; Triglycerides; Weight Loss

The beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear. We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity.. Mice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg x kg(-1) x day(-1)) for 6 weeks.. Treatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism.. A reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716.

Topics: Adiponectin; Adipose Tissue; Animal Feed; Animals; Apolipoproteins A; Apolipoproteins B; Body Weight; Cannabinoid Receptor Antagonists; Diet; Fatty Liver; Gene Expression Regulation; Liver; Mice; Mice, Obese; Obesity; Organ Size; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sucrose

The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-4F. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyperleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-4F prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit.

Topics: Actins; Animals; Apolipoprotein A-I; Body Weight; Cells, Cultured; Diet; Disease Models, Animal; Fatty Liver; Hepatocytes; Inflammation; Liver; Liver Cirrhosis; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Organ Size; Piperidines; Pyrazoles; Rimonabant

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Disease Models, Animal; Disease Progression; Endocannabinoids; Fatty Liver; Glycolysis; Hepatitis C, Chronic; Hepatocytes; Humans; Hypertension, Portal; Lipogenesis; Liver; Liver Cirrhosis; Liver Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

Topics: Animals; Cannabinoid Receptor Antagonists; Fatty Liver; Inflammation; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Adult; Blood Glucose; Fatty Liver; Female; Humans; Insulin; Lipids; Liver; Mitochondria, Liver; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Severity of Illness Index; Treatment Outcome

Topics: Animals; Clofibrate; Diet; Electrophoresis; Ethylamines; Fatty Liver; Glucosephosphate Dehydrogenase; Hepatomegaly; Hypolipidemic Agents; Lipoproteins; Liver; Male; Methylamines; Naphthalenes; Orotic Acid; Phenols; Piperidines; Propionates; Rats; Rats, Inbred Strains; Sulfonamides; Sulfonic Acids; Thyroxine