CNS ACTION OF APPETITE SUPPRESSANT AMINOSTEROL
S Rexford, Assoc Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01DK062348-08 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: 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
Keywords: adenylate kinase; Adipose tissue; Adverse effects; Agonist; Amygdaloid structure; Animals; Appetite Depressants; Applications Grants; Area; Arthritis; Attenuated; Binding (Molecular Function); Body Weight decreased; Brain; Cardiovascular Diseases; Cell Nucleus; Cholelithiasis; Corticotropin-Releasing Hormone; Data; db/db mouse; Desire for food; Diabetes Mellitus; Diet; diet and exercise; Eating; energy balance; Energy Metabolism; Enzymes; Epidemic; Excess Mortality; Failure (biologic function); fatty acid oxidation; Fatty Liver; Fatty-acid synthase; feeding; food consumption; Functional disorder; Genetic; Glucose; Goals; Grant; Homeostasis; Hyperlipidemia; Hypothalamic structure; immunoreactivity; improved; in vivo; Incidence; Injection of therapeutic agent; insight; Insulin; insulin sensitivity; insulin signaling; intraperitoneal; Ion Channel; Lampreys; Lateral; Leptin; Life; Life Style; Link; lipid metabolism; Lipids; Lipolysis; Liver; Liver diseases; Malignant Neoplasms; Mediating; Melanocortin 4 Receptor; Membrane; Metabolic; Metabolism; MSI1436; Mus; Muscle; Neurons; neuropeptide Y; non-alcoholic fatty liver; Non-Insulin-Dependent Diabetes Mellitus; novel; Nucleus solitarius; Obese Mice; Obesity; Obesity associated disease; obesity treatment; paraventricular nucleus; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pheromone; prevent; Property; Rattus; receptor; Receptor Gene; Receptor Signaling; reproductive; response; Risk; Rodent; Role; sedentary; SHU 9119; Signal Transduction; Sleep Apnea Syndromes; Starvation; Steroids; Surface; System; Thermogenesis; Triglycerides; United States; Weight; Xenopus oocyte
Project start date: 2002-07-15
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2012
5R01DK062348-08 (2010): $304169
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to S Rexford
CNS ACTION OF APPETITE SUPPRESSANT AMINOSTEROL
S Rexford, Assoc Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 3R01DK062348-06S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This award is issued in response to Notice OD-09-060, Recovery Act Administrative Supplements Providing Summer Research Experiences for Students and Science Educators. 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
Keywords: adenylate kinase; Adipose tissue; Adverse effects; Agonist; Amygdaloid structure; Animals; Appetite Depressants; Applications Grants; Area; Arthritis; Attenuated; Binding (Molecular Function); Body Weight decreased; Brain; Cardiovascular Diseases; Cell Nucleus; Cholelithiasis; Corticotropin-Releasing Hormone; Data; db/db mouse; Desire for food; Diabetes Mellitus; Diet; diet and exercise; Eating; energy balance; Energy Metabolism; Enzymes; Epidemic; Excess Mortality; Failure (biologic function); fatty acid oxidation; Fatty Liver; Fatty-acid synthase; feeding; food consumption; Functional disorder; Genetic; Glucose; Goals; Grant; Homeostasis; Hyperlipidemia; Hypothalamic structure; immunoreactivity; improved; in vivo; Incidence; Injection of therapeutic agent; insight; Insulin; insulin sensitivity; insulin signaling; intraperitoneal; Ion Channel; Lampreys; Lateral; Leptin; Life; Life Style; Link; lipid metabolism; Lipids; Lipolysis; Liver; Liver diseases; Malignant Neoplasms; Mediating; Melanocortin 4 Receptor; Membrane; Metabolic; Metabolism; MSI1436; Mus; Muscle; Neurons; neuropeptide Y; non-alcoholic fatty liver; Non-Insulin-Dependent Diabetes Mellitus; novel; Nucleus solitarius; Obese Mice; Obesity; Obesity associated disease; obesity treatment; paraventricular nucleus; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pheromone; prevent; Property; Rattus; receptor; Receptor Gene; Receptor Signaling; reproductive; response; Risk; Rodent; Role; sedentary; SHU 9119; Signal Transduction; Sleep Apnea Syndromes; Starvation; Steroids; Surface; System; Thermogenesis; Triglycerides; United States; Weight; Xenopus oocyte
Project start date: 2002-07-15
Project end date: 2011-05-31
Budget start date: 23-JUN-2009
Budget end date: 31-MAY-2011
3R01DK062348-06S1 (2009): $18270
3R01DK062348-07S1 (2010): $53158
CNS EFFECTS OF ADIPOKINES ON METABOLISM
S Rexford, Assoc Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Abstract: Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may provide key insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acid oxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulin sensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increase energy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have direct actions on liver and muscle, but recent observations suggest that these adipokines also have central effects. We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part, through distinct neuronal targets and signaling pathways in the hypothalamus. Specific Aim 1 will compare the effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. We will examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics. Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin in agouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucose levels is mediated through melanocortin (MC)4 receptor signaling. Specific Aim 2 will determine the sites of action of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situ hybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin, adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test the hypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin on metabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding the hypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will provide novel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic and treatment strategies
Keywords: 5`-AMP-activated protein kinase; adenylate kinase; Adipocytes; adipokines; adiponectin; Attenuated; attenuation; base; blood glucose regulation; Cardiovascular Diseases; Chemicals; Corticotropin-Releasing Hormone; Cytokine Inducible SH2-Containing Protein; Data; Degenerative polyarthritis; Desire for food; Diabetes Mellitus; Disease; energy balance; Energy Metabolism; Epidemic; Event; fatty acid oxidation; feeding; Functional disorder; Genetic; Glucose; glucose metabolism; Hormonal; Hormones; Hypothalamic structure; Immunohistochemistry; immunoreactivity; In Situ Hybridization; increased appetite; innovation; insight; Insulin; Insulin Resistance; insulin sensitivity; Kinetics; Leptin; Link; Lipids; Lipolysis; Liver; Malignant Neoplasms; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolism; Morbidity - disease rate; Mus; Muscle; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; novel; novel diagnostics; Obesity; Obesity associated disease; paraventricular nucleus; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Prevention strategy; Proteins; public health medicine (field); Radioactive Tracers; Receptor Signaling; Regulation; resistin; Signal Pathway; Signal Transduction; Site; Sleep Apnea Syndromes; Testing; Thermogenesis; Thyrotropin-Releasing Hormone; Tissues; treatment strategy; United States
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
5P01DK049210-15_0012 (2010): $295318
MOUSE PHENOTYPING, PHYSIOLOGY, AND METABOLISM CORE
S Rexford, Assoc Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Abstract: MOUSE PHENOTYPING, PHYSIOLOGY, AND METABOLISM CORE Director - R. Ahima Our understanding of the pathogenesis of diabetes has benefited from the use of gene targeting methodology in mice to elucidate molecular mechanisms. However, such efforts are often hampered by an absence of a clear metabolic phenotype. Failure to identify a phenotype may be due to lack of expertise and/or facilities for evaluating metabolic changes in mice. The Mouse Phenotyping, Physiology and Metabolism Core provides investigators of the Penn Diabetes and Endocrinology Research Center (DERC) with state-of-the-art, timely and cost-effective diagnostic studies in mice. The core offers consultation and experimental design, monitoring of feeding, energy expenditure and locomotor activity using the Comprehensive Laboratory Animal Monitoring System (CLAMS), treadmill exercise using the Oxymax system, and measurement of body composition using dual emission x-ray absorptiometry (DEXA) and carcass chemistry. Glucose homeostasis is assessed by oral or intraperitoneal (i.p.) glucose administration, and whole body insulin sensitivity by i.p. insulin injection. Insulin clamp and radioactive tracers are used to assess glucose fluxes and tissue specific glucose uptake. Studies in the core are performed by two research specialists under the direction of Rex Ahima. Future plans for the core include the use magnetic resonance (MRI) for measurement of water, lean and fat content, assessment of in vivo lipid kinetics, and employment of an additional technician to expedite services. The Mouse Phenotyping, Physiology and Metabolism Core will maintain a databank of metabolic and hormonal parameters in mouse models of diabetes and obesity, and coordinate its activities with other core laboratories, i.e. Islet Cell Biology (Franz Matschinsky), Radioimmunoassay/Biomarkers (Bryan Wolf; Muredach Reilly), Transgenic and Chimeric Mouse (Nancy Cooke), and Genomics and Gene Targeting Cores (Klaus Kaestner). These efforts will result in optimum data acquisition and metabolic phenotyping of mice, and facilitate the translation of ideas from the bench to mice, and ultimately to humans
Keywords: biomarker; blood glucose regulation; Body Composition; Bone Tissue; Cellular biology; Chemicals; Chemistry; Consult; Consultations; cost effective; Coupled; Data; data acquisition; Data Collection; Databases; design; Diabetes Mellitus; Diabetic mouse; Diagnostic; Diagnostic Services; Diagnostic tests; Diet; Dose; drinking; Employment; Endocrinology; Energy Metabolism; Ensure; Environmental Risk Factor; Equipment; Exercise; Experimental Designs; Failure (biologic function); Fatty acid glycerol esters; Fee-for-Service Plans; feeding; Funding; Funding Agency; Future; Gene Targeting; Genomics; Glucose; glucose tolerance; glucose uptake; Home environment; Hormonal; Housing; Human; Human Resources; in vivo; Injection of therapeutic agent; instrument; Insulin; Insulin Resistance; insulin sensitivity; insulin tolerance; intraperitoneal; Intravenous; Islet Cell; Kinetics; Knockout Mice; Laboratories; Laboratory Animals; Laboratory mice; Light; Lipids; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; meetings; member; Metabolic; Metabolism; Methodology; Mission; Molecular; Monitor; Motor Activity; mouse model; Mus; Muscle; Mutant Strains Mice; Neonatal; Obese Mice; Obesity; operation; Oral; Oxygen Consumption; Pathogenesis; Pharmacological Treatment; phenome; Phenotype; Physiological; Physiology; Procedures; Radioactive Tracers; Radioimmunoassay; Research; Research Personnel; research study; respiratory; Rest; Screening procedure; Services; Specialist; System; Temperature; Testing; The Jackson Laboratory; Tissues; Transgenic Organisms; Translations; United States National Institutes of Health; Water; web site; Wolves
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P30DK019525-35_9011 (2011): $218215
5P30DK019525-34_9011 (2010): $240777
MOUSE METABOLIC PHENOTYPING CORE
S Rexford, Assoc Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Keywords: Arts; Atherosclerosis; blood glucose regulation; Body Composition; Cellular biology; Cessation of life; Chemistry; Circadian Rhythms; cost; Coupled; Data; Data Collection; Databases; design; Diabetes Mellitus; Diagnostic Services; Diagnostic tests; Diet; Disease; drinking; Endocrinology; energy balance; Ensure; Equipment; Evaluation; Exercise; Fatty Acids; feeding; functional genomics; Funding; Gender; Gene Dosage; Gene Targeting; Genes; Genetic; Glucose; glucose disposal; glucose tolerance; glucose uptake; Growth; Heterozygote; Home environment; Homeostasis; Housing; Human Resources; Hypertriglyceridemia; in vivo; Insulin; Insulin Receptor; Islet Cell; Knock-out; Laboratories; Laboratory Animals; Lipids; lipoprotein disorder; Location; Maintenance; Measurement; Metabolic; metabolic abnormality assessment; Monitor; Motor Activity; Mouse Strains; Mus; Muscle; Neonatal; sterified Fatty Acids; Obesity; Pathogenesis; phenome; Phenotype; Phosphorylation; Physiological; Procedures; Quality Control; Radioimmunoassay; ranpirnase; Research; Research Personnel; research study; Resources; Services; Skeletal muscle structure; square foot; Stress; Study models; System; Technology; Telemetry; Temperature; Tissues; Training; Transgenic Organisms; Wages
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
5P01DK049210-15_9004 (2010): $73834