CNS action of appetite suppressant aminosterol

食欲抑制剂氨基甾醇的中枢神经系统作用

• 批准号: 7994605
• 负责人: REXFORD S. AHIMA
• 金额: $ 5.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994605
• 关键词: Adipose tissue; Adverse effects; Agonist; Amygdaloid structure; Animals; Appetite Depressants; Applications Grants; Area; Arthritis; Attenuated; Binding; Body Weight decreased; Brain; Cardiovascular Diseases; Cell Nucleus; Cholelithiasis; Corticotropin-Releasing Hormone; Data; Desire for food; Diabetes Mellitus; Diet; Eating; Energy Metabolism; Enzymes; Epidemic; Excess Mortality; Failure; Fatty Liver; Fatty-acid synthase; Functional disorder; Genetic; Glucose; Goals; Grant; Homeostasis; Hyperlipidemia; Hypothalamic structure; Incidence; Injection of therapeutic agent; Insulin; Ion Channel; Lampreys; Lateral; Leptin; Life; Life Style; Link; Lipids; Lipolysis; Liver; Liver diseases; MSI1436; Malignant Neoplasms; Mediating; Melanocortin 4 Receptor; Membrane; Metabolic; Metabolism; Mus; Muscle; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Obese Mice; Obesity; Obesity associated disease; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pheromone; Property; Rattus; Receptor Gene; Receptor Signaling; Risk; Rodent; Role; SHU 9119; Signal Transduction; Sleep Apnea Syndromes; Starvation; Steroids; Surface; System; Thermogenesis; Triglycerides; United States; Weight; Xenopus oocyte; adenylate kinase; db/db mouse; diet and exercise; energy balance; fatty acid oxidation; feeding; food consumption; immunoreactivity; improved; in vivo; insight; insulin sensitivity; insulin signaling; intraperitoneal; lipid metabolism; neuropeptide Y; non-alcoholic fatty liver; novel; obesity treatment; paraventricular nucleus; prevent; receptor; reproductive; response; sedentary

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.

描述（由申请人提供）：肥胖的流行与增加有关