neuropeptide-y and Fatty-Liver

A gain-of-function polymorphism in human neuropeptide Y (

Topics: Adrenergic Neurons; Animals; Cholesterol; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Fatty Acids; Fatty Liver; Gene Expression; Glucose; Hypercholesterolemia; Liver; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Sympathetic Nervous System

Nonalcoholic fatty liver disease is one of the most common complications of obesity. Mulberry is an important source of phytochemicals, such as anthocyanins, polyphenols and flavonoids, which are related to its antioxidant activity. In this study, we developed a hypothesis that mulberry exerted beneficial effects on metabolic disorders and evaluated the influence of the mulberry ethanol extract (MEE) on high-fat diet-induced hepatic steatosis and insulin resistance in mice. Thirty-six male C57BL/6J mice were assigned into 3 groups and fed either a low-fat diet or a high-fat diet with or without supplementation with MEE. Our results showed that administration of MEE reduced diet-induced body weight gain, improved high-fat diet-induced hepatic steatosis and adipose hypertrophy, alleviated insulin resistance, and improved glucose homeostasis. Analysis of hepatic gene expression indicated that MEE treatment changed the expression profile of genes involved in lipid and cholesterol metabolism. In conclusion, the present study demonstrated that MEE supplementation protected mice from high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, the protective effects of MEE were associated with the induction of fatty acid oxidation and decreased fatty acid and cholesterol biosynthesis.

Topics: Adiposity; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Blood Glucose; Cholesterol; Diet, Fat-Restricted; Diet, High-Fat; Ethanol; Fatty Liver; Fruit; Insulin; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Morus; Neuropeptide Y; Phytochemicals; Plant Extracts; Triglycerides; Weight Gain

Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. NAFLD may lead to cirrhosis. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood.. to determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers.. Freshly isolated hHSC were assessed for expression of cathecholamine/neuropeptide Y receptors and for the synthesis of NE/EPI. The effects of NE/EPI/NPY and adrenoceptor antagonists prazosin (PRZ)/propranolol (PRL) on hHSC fibrogenic functions and the involved kinases and interleukin pathways were examined. Human livers with proven NAFLD were then assessed for upregulation of SNS signalling components.. Activated hHSC express functional α/β-adrenoceptors and NPY receptors, which are upregulated in the livers of patients with cirrhotic NAFLD. hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival. Exogenous NE/EPI and NPY dose-dependently induced hHSC proliferation, mediated via p38 MAP, PI3K and MEK signalling. NE and EPI but not NPY increased expression of collagen-1α2 via TGF-β without involvement of the pro-fibrogenic cytokines leptin, IL-4 and IL-13 or the anti-fibrotic cytokine IL-10.. hHSC synthesize and require cathecholamines for optimal survival and fibrogenic functionality. Activated hHSC express directly fibrogenic α/β-adrenoceptors and NPY receptors, upregulated in human cirrhotic NAFLD. Adrenoceptor and NPY antagonists may be novel anti-fibrotic agents in human NAFLD.

Topics: Base Sequence; Catecholamines; Cells, Cultured; Chromatography, High Pressure Liquid; Collagen; DNA Primers; Fatty Liver; Hepatic Stellate Cells; Humans; Interleukins; Liver Cirrhosis; Neuropeptide Y; Non-alcoholic Fatty Liver Disease; Norepinephrine; Receptors, Adrenergic; Reverse Transcriptase Polymerase Chain Reaction; Sympathetic Nervous System; Transforming Growth Factor beta; Up-Regulation

Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.

Topics: Adiposity; Agouti-Related Protein; Animals; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fatty Liver; Glycerol-3-Phosphate O-Acyltransferase; Insulin Resistance; Mice; Mice, Inbred Strains; Mitochondria, Liver; Neuropeptide Y; Obesity; Oxygen Consumption; Thinness; Triglycerides

The complexity pathogenesis in the nonalcoholic fatty liver disease (NAFLD) involves an interplay between adipokines and neuroendocrine regulation of energy balance, including the role of neuropeptide Y (NPY)/agouti-related protein (AgRP) system. The first aim of this study was to assess the effect of long-term interdisciplinary intervention on NAFLD in obese adolescents, and the second objective was to establish the relationship between NPY/AgRP ratio and adiponectinemia. Fifty-five postpuberty obese adolescents were submitted to interdisciplinary intervention. The group was divided between subjects with and without NAFLD (n = 19 and 36, respectively). Blood samples were collected to measure glycemia, hepatic transaminases, lipid profile, insulin resistance, and sensitivity. Adiponectin, NPY, and AgRP concentrations were measured by enzyme-linked immunosorbent assay. Food intake was measured using 3-day diet records. It was observed at baseline that important clinical parameters including body weight, body mass index, visceral fat, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, triglycerides, very low-density lipoprotein cholesterol, and hepatic transaminases were more altered in NAFLD patients. After the intervention, these parameters, total energy, and macronutrient intake were reduced significantly in both groups. The most important finding was the positive correlation between AgRP and visceral fat in all patients and the negative correlation between NPY/AgRP and adiponectinemia only in NAFLD obese adolescents. The NAFLD patients presented more altered clinical parameters than the non-NAFLD subjects, including the negative correlation between adiponectinemia and NPY/AgRP. These results suggested that NAFLD obese adolescents presented an inflammatory profile that can influence the neuroendocrine regulation of energy balance, suggesting an additional impairment in the weight loss therapy.

Topics: Adiponectin; Adolescent; Agouti-Related Protein; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Fatty Liver; Female; gamma-Glutamyltransferase; Humans; Insulin; Intra-Abdominal Fat; Male; Neuropeptide Y; Obesity; Statistics, Nonparametric; Triglycerides; Ultrasonography; Weight Loss; Young Adult

Little progress has been made to identify the central neuroendocrine pathway involved in the energy intake control in nonalcoholic fatty liver disease (NAFLD) patients.. To assess the influence of orexigenic neuropeptides in the nutritional aspects of NAFLD obese adolescents submitted to a long-term interdisciplinary approach.. Fifty adolescents aged 15-19 years, with body mass index at least 95th percentile, consisting of 25 patients without NAFLD and 25 with NAFLD. The NAFLD diagnosis was determined by ultrasonography. Blood samples were collected to analyze glycemia, hepatic transaminases, and lipid profile. Insulin resistance was estimated by Homeostasis Model Assessment Insulin Resistance Index. Neuropeptide Y (NPY) and agouti related protein concentrations were measured by enzyme-linked immunosorbent assay. Analyses of food intake were made by 3 days recordatory inquiry.. At baseline conditions, the patients with NAFLD had significantly higher values of body mass, body mass index, visceral fat, triglycerides, VLDL-C, and hepatic transaminases. After the long-term intervention, they presented a significant reduction in these parameters. In both the groups, it was observed a significant decrease in energy intake, macronutrients and dietetic cholesterol. Only the patients with NAFLD presented a positive correlation between the saturated fatty acids intake and the orexigenic neuropeptides NPY and agouti related protein, and carbohydrate with NPY. Indeed, it was observed a positive correlation between energy intake, lipid (%) and saturated fatty acids with visceral fat accumulation.. Our findings showed an important influence of diet composition in the orexigenic system, being essential consider that the excessive saturated fatty acids intake could be a determinant factor to increase nonalcoholic fatty liver disease.

Topics: Adolescent; Agouti-Related Protein; Eating; Energy Metabolism; Exercise; Fatty Acids; Fatty Liver; Female; Humans; Intra-Abdominal Fat; Male; Neuropeptide Y; Nutrition Assessment; Obesity; Subcutaneous Fat; Ultrasonography; Young Adult

Topics: Amyloid; Anti-Obesity Agents; Appetite; Bariatric Surgery; Diabetes Complications; Diabetes Mellitus; Diet, Carbohydrate-Restricted; Fatty Liver; Female; Gastric Emptying; Humans; Insulin; Islet Amyloid Polypeptide; Lipolysis; Male; Neuropeptide Y; Obesity