MOUSE PHENOTYPING, PHYSIOLOGY, AND METABOLISM CORE
Rexford S Ahima, Associate Professor
University Of Pennsylvania
3451 Walnut Street
philadelphia, Pa 19104
Grant 5P30DK019525-329011 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Keywords: metabolism, physiology
Sponsored Links Excellgen http://Excellgen.com
MOUSE PHENOTYPING, PHYSIOLOGY, AND METABOLISM CORE
Rexford S Ahima, Assoc Professor A
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Grant 5P30DK019525-33_9011 from National Institute Of Diabetes And Digestive And Kidney Diseases
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: Animals, Laboratory; Arts; Body Composition; Body Tissues; Bone Tissue; Cellular biology; Chemicals; Chemistry; Consult; Consultations; Coupled; D-Glucose; Data; Data Banks; Data Bases; Data Collection; Databank, Electronic; Databanks; Database, Electronic; Databases; Dextrose; Diabetes Mellitus; Diabetic mouse; Diagnostic; Diagnostic Services; Diagnostic tests; Diet; Dose; Employment; Endocrinology; Energy Expenditure; Energy Metabolism; Ensure; Environmental Factor; Environmental Risk Factor; Equipment; Exercise; Exercise, Physical; Experimental Designs; FLR; Failure (biologic function); Fats; Fatty acid glycerol esters; Fee-for-Service Plans; Fees for Service; Funding; Funding Agency; Funding Source; Future; Gene Targeting; Genomics; Glucose; Home; Home environment; Hormonal; Housing; Human; Human Resources; Human, General; Humulin R; Hydrogen Oxide; Immunologic, Radioimmunoassay; Injection of therapeutic agent; Injections; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Resistance; Insulin, Regular; Intermediary Metabolism; Intravenous; Investigators; Islet Cell; Kinetic; Kinetics; Knockout Mice; Laboratories; Laboratory Animals; Laboratory mice; Lipids; Locomotor Activity; METBL; MR Imaging; MR Tomography; MRI; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Mammals, Mice; Man (Taxonomy); Man, Modern; Manpower; Measurement; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Metabolic; Metabolic Processes; Metabolism; Metabolism and Endocrinology; Method LOINC Axis 6; Methodology; Mice; Mice, Knock-out; Mice, Knockout; Mice, Mutant Strains; Mice, Obese; Mission; Molecular; Monitor; Motor Activity; Murine; Mus; Muscle; Muscle Tissue; Mutant Strains Mice; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Neonatal; Novolin R; Nuclear Magnetic Resonance Imaging; Null Mouse; Obese Mice; Obesity; Operation; Operative Procedures; Operative Surgical Procedures; Oral; Oxygen Consumption; Pathogenesis; Pharmacological Treatment; Phenotype; Physiologic; Physiological; Physiology; Procedures; RIA; Radioactive Tracers; Radioimmunoassay; Research; Research Personnel; Researchers; Rest; Science of Chemistry; Screening procedure; Services; Specialist; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Targetings, Gene; Temperature; Testing; Tissues; Transgenic Organisms; Translations; United States National Institutes of Health; Water; Wolves; Zeugmatography; adiposity; biomarker; blood glucose regulation; cell biology; clinical data repository; clinical data warehouse; corpulence; corpulency; corpulentia; cost; data acquisition; data repository; design; designing; diabetes; diagnosis service; drinking; environmental risk; experiment; experimental research; experimental study; failure; feeding; glucose control; glucose homeostasis; glucose regulation; glucose uptake; in vivo; instrument; insulin resistant; insulin sensitivity; insulin tolerance; intraperitoneal; meetings; member; mouse model; mouse model of diabetes; mouse mutant; obese; obese people; obese person; obese population; personnel; phenome; relational database; research study; respiratory; screening; screenings; surgery; transgenic; web site
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2010
PFA/PA: RFA-DK-06-012
5P30DK019525-33_9011 (2009): $294586
Grants awarded to Rexford S Ahima
CNS Action Of Appetite Suppressant Aminosterol
Rexford S Ahima, Associate Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 5R01DK062348-03 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: END
Abstract: The prevalence of obesity in the United States has reached epidemic proportions and poses enormous public health challenges, as obesity is a major risk factor for type 2 diabetes, hypertension, cardiovascular disease and cancer, as well as an independent risk factor for mortality. Although diet and exercise are essential to weight management, it has become increasingly clear that a large proportion of patients would require drug treatment to decrease and maintain body weight. The goal of this grant is to understand the action of a novel cholesterol derivative with potent anti-obesity and anti-diabetic properties. MSI- 1436 is an aminosterol which we have found to cause reversible suppression of food intake, increased energy expenditure and normalization of glucose levels when administered by peripheral and more potently intracerebroventricular injection to rodents. Unlike other anorectics, a single injection of MSI-1436 produces a prolonged effect lasting several days. MSI- 1436 is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice, suggesting that leptin signaling is not critical to its action. By contrast, MSI-1436 effect is blunted in agouti (Ay/a) mice, suggesting that its central action may involve the melanocortin pathway. Although acute MSI1436 administration strongly induces Fos-immunoreactivity in the paraventricular nucleus and to a lesser extent in the arcuate, ventromedial and pre-mammillary nuclei, the neuronal circuitry mediating the anti-obesity vs anti-diabetic effects of MSI-1436 is not known. We hypothesize that MSI-1436 enters the braii via a specific transport mechanism and engages hypothalamic neuronal targets to regulate energy balance and glucose homeostasis. Specific Aim 1 involves the injection of MSI-1436 into specific hypothalamic nuclei to determine which sites mediate the effects on feeding, body weight and glucose levels. Specific Aim 2 will analyze the distribution of MSI-1436 binding sites and determine the chemical phenotypes 01 MSI-1436 responsive neurons. Specific Aim 3 will determine the contribution of the central melanocortin system by analyzing MSI-1436 response in melanocortin receptor (MCR)-3 and 4 knockout mice. Finally, Specific Aim 4 will utilize GeneChip microarray to determine whether MSI-1436 regulates novel hypothalamic genes. Putative MS-1436 targets will be validated in multiple mouse models. Together these studies will provide insights into the mechanisms underlying MSI-1436 action in the brain. Understanding the basis for the novel effects of MSI-1436 on feeding behavior, body weight and glucose will greatly enhance the field of obesity and metabolism. New pathways affected by MSI-1436 may elucidate novel cellular targets for the treatment of obesity.
Keywords: appetite, bioenergetics, cholestane compound, glucose metabolism, obesity, weight control agent, binding site, biological transport, homeostasis, hormone receptor, hypothalamus, melanocyte stimulating hormone, neurochemistry, neuron, nutrient intake activity, pharmacokinetics, genetically modified animal, immunocytochemistry, in situ hybridization, laboratory mouse, microarray technology, northern blotting, nutrition related tag
Project start date: 2002-07-15
Project end date: 2006-03-31
5R01DK062348-03 (2004): $262516
5R01DK062348-07 (2009): $307242
5R01DK062348-06 (2008): $328725
5R01DK062348-05 (2007): $313512
2R01DK062348-04A1 (2006): $321850
2R56DK062348-04 (2005): $79250
CNS EFFECTS OF ADIPOKINES ON METABOLISM
Rexford S Ahima, Assoc Professor A
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
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: (hydroxymethylglutaryl-CoA reductase (NADPH)) kinase; 5`-AMP-activated protein kinase; 5-Oxo-L-prolyl-L-histidyl-L-prolinamide; ACRP30 protein; ACTH-Releasing Factor; AMP Kinase; AMP-activated kinase; AMP-activated protein kinase; AMPK enzyme; ATP-AMP Phosphotransferase; ATP-AMP Transphosphorylase; Adenylokinase; Adipocytes; Adipose Cell; Apnea, Sleep; Appetite; Appetite stimulated; Arthritis, Degenerative; Attenuated; Body Tissues; CIS protein; CIS-1 Protein; CISH; CISH Protein; CRF-41; CRH; Cancers; Cardiovascular Diseases; Cell Communication and Signaling; Cell Signaling; Cell/Tissue, Immunohistochemistry; Chemicals; Chemotherapy-Hormones/Steroids; Corticoliberin; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone-41; Cytokine Inducible SH2-Containing Protein; Cytokine-Inducible Inhibitor of Signaling Type 1B; D-Glucose; Data; Degenerative polyarthritis; Desire for food; Dextrose; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Disease; Disorder; Dysfunction; Endocrine Gland Secretion; Energy Expenditure; Energy Metabolism; Epidemic; Event; Fat Cells; Functional disorder; G18; Genetic; Genetics, in situ Hybridization; Glucose; HMG CoA reductase (NADPH) kinase; HMG CoA reductase kinase; HMG coenzyme A reductase (NADPH) kinase; Heat Production; Hormonal; Hormones; Humulin R; Hypothalamic structure; Hypothalamus; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; In Situ Hybridization; Increased food appetite; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Resistance; Insulin, Regular; Intermediary Metabolism; Intracellular Communication and Signaling; Kinetic; Kinetics; Leptin; Link; Lipids; Lipocytes; Lipolysis; Liver; MC4 Receptor; METBL; MODY; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mature Lipocyte; Mature fat cell; Maturity-Onset Diabetes Mellitus; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic Processes; Metabolism; Mice; Morbidity; Morbidity - disease rate; Murine; Mus; Muscle; Muscle Tissue; Myokinase; NIDDM; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; Neuropeptides; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Novolin R; Nutrition; Nutritional Science; Ob Gene Product; Ob Protein; Obese Gene Product; Obese Protein; Obesity; Obesity associated disease; Obesity related disease; Osteoarthritis; Osteoarthrosis; Paraventricular Hypothalamic Nucleus; Paraventricular Nucleus; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Physiopathology; Prevention strategy; Preventive strategy; Proteins; Protirelin; Protyreline; Public Health; Pyr-His-ProNH2; Radioactive Tracers; Receptor Signaling; Receptor, Melanocortin, Type 4; Regulation; SOCS; Science of nutrition; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; Sleep Apnea Syndromes; Sleep Hypopnea; Sleep-Disordered Breathing; Structure of paraventricular nucleus; Suppressor of Cytokine Signaling; T2D; T2DM; TRH; Testing; Therapeutic Hormone; Thermogenesis; Thyroid-Releasing Hormone; Thyrotropin-Releasing Hormone; Tissues; Type 2 diabetes; Type II diabetes; United States; adenylate kinase; adipocyte complement-related protein 30-kDa; adipocyte, C1q and collagen domain containing protein; adipokines; adiponectin; adiposity; adult onset diabetes; apM-1 protein; apM1 (adipose-specific) protein; attenuation; base; biological signal transduction; blood glucose regulation; body system, hepatic; cardiovascular disorder; corpulence; corpulency; corpulentia; corticotropin releasing hormone; degenerative joint disease; diabetes; disease/disorder; energy balance; fatty acid oxidation; feeding; gene product; glucose control; glucose homeostasis; glucose metabolism; glucose regulation; hydroxymethylglutaryl-CoA-reductase kinase; hypertrophic arthritis; hypothalamic; immunoreactivity; in situ Hybridization Staining Method; increased appetite; increased hunger; innovate; innovation; innovative; insight; insulin resistant; insulin sensitivity; ketosis resistant diabetes; malignancy; maturity onset diabetes; neoplasm/cancer; neuronal; new diagnostics; next generation diagnostics; novel; novel diagnostics; nutrition; ob/ob mouse; obese; obese people; obese person; obese population; organ system, hepatic; paraventricular nucleus; pathophysiology; pathway; public health medicine (field); resistin; treatment strategy
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
5P01DK049210-14_0012 (2009): $298301
Core--Phenotyping, Physiology, And Metabolism Core
Rexford S Ahima, Associate Professor
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
Grant 2P30DK019525-269011 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Diabetes is highly prevalent in the United States and is associated with increased morbidity from cardiovascular, renal, neurological and other complications. Our understanding of the pathogenesis of diabetes has benefited immensely from pharmacological, dietary and genetic manipulations in mice and other rodents. Despite the rapid increase in the use of gene targeting methodology to elucidate the molecular mechanisms mediating diabetes in mice, such efforts are often hampered by the absence of a clear phenotype. Failure to demonstrate a phenotype is attributable in part to the lack of expertise and/or facilities for evaluating physiologic and metabolic features in mice. We propose to establish a Mouse Phenotyping, Physiology and Metabolism Core, with the objective of providing investigators of the Penn Diabetes Center with state-of-the-art, timely and cost-effective diagnostic studies in mice. The core will offer services for analyzing glucose homeostasis, feeding behavior and energy balance, body composition, blood chemistry and hemodynamics. Activities of the core will be carried out by 2 technicians under the direction of Dr. Rex Ahima. The Phenotyping Core will maintain a databank of physiological, hormonal and metabolic measurements in mouse models of diabetes and obesity, and offer advice and training on various aspects of mouse physiology. Activities of the core will be coordinated with other core laboratories, Le Islet Cell Biology (Franz Matschinsky), Radioimmunoassay (Bryan Wolf), Transgenic and Chimeric (Nancy Cooke and Functional Genomics (Klaus Kaestner). These efforts will result in optimum data acquisition in diabetic mouse models, and facilitate the translation of ideas from the bench to mice and ultimately to humans.
Keywords: bioenergetics, biomedical facility, diabetes mellitus, glucose metabolism, phenotype, blood chemistry, blood glucose, body composition, hemodynamics, insulin, obesity, glucose clamp technique, glucose tolerance test, laboratory mouse, scintillation counter, telemetry, tissue /cell culture, transgenic animal
Project start date: 1977-03-01
Project end date: 2007-02-28
MOUSE METABOLIC PHENOTYPING CORE
Rexford S Ahima, Assoc Professor A
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Keywords: Abnormal Assessment of Metabolism; Animals, Laboratory; Arts; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Autoregulation; Body Composition; Body Tissues; Cellular biology; Cessation of life; Chemistry; Circadian Rhythms; Coupled; D-Glucose; Data; Data Banks; Data Bases; Data Collection; Databank, Electronic; Databanks; Database, Electronic; Databases; Death; Dextrose; Diabetes Mellitus; Diagnostic Services; Diagnostic tests; Diet; Disease; Disorder; Diurnal Rhythm; Endocrinology; Ensure; Equipment; Evaluation; Exercise; Exercise, Physical; Fatty Acids; Fatty Acids, sterified; Free Fatty Acids; Funding; Gender; Gene Copy Number; Gene Dosage; Gene Targeting; Generalized Growth; Genes; Genetic; Glucose; Growth; Heterozygote; Home; Home environment; Homeostasis; Housing; Human Resources; Humulin R; Hyperglyceridemia; Hypertriglyceridemia; INSR; Immunologic, Radioimmunoassay; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Receptor; Insulin Receptor Protein-Tyrosine Kinase; Insulin, Regular; Insulin-Dependent Tyrosine Protein Kinase; Intermediary Metabolism; Investigators; Islet Cell; Knock-out; Knockout; Laboratories; Laboratory Animals; Lipids; Location; Locomotor Activity; METBL; Maintenance; Maintenances; Mammals, Mice; Manpower; Measurement; Metabolic; Metabolic Processes; Metabolic Studies; Metabolism; Metabolism Studies; Metabolism and Endocrinology; Mice; Monitor; Motor Activity; Mouse Strains; Murine; Mus; Muscle; Muscle Tissue; Muscle, Skeletal; Muscle, Voluntary; Neonatal; sterified Fatty Acids; Novolin R; Nutrition; Nutritional Science; Nyctohemeral Rhythm; Obesity; P-30; P-30 Protein; P30; P30 Protein; Pathogenesis; Phenotype; Phosphorylation; Physiologic; Physiological; Physiological Homeostasis; Procedures; Protein Phosphorylation; Quality Control; RIA; Radioimmunoassay; Raised TG; Raised triglycerides; Research; Research Personnel; Research Resources; Researchers; Resources; Salaries; Science of Chemistry; Science of nutrition; Services; Skeletal Muscle Tissue; Skeletal muscle structure; Stress; Study models; System; System, LOINC Axis 4; Targetings, Gene; Technology; Telemetries; Telemetry; Temperature; Tissue Growth; Tissues; Training; Transgenic Organisms; Triglyceride increased; Triglycerides high; Twenty-Four Hour Rhythm; Wages; adiposity; atheromatosis; atherosclerotic vascular disease; blood glucose regulation; cell biology; circadian; circadian process; clinical data repository; clinical data warehouse; corpulence; corpulency; corpulentia; cost; daily biorhythm; data repository; design; designing; diabetes; diagnosis service; disease/disorder; diurnal variation; drinking; elevated tg; elevated triglyceride; energy balance; experiment; experimental research; experimental study; feeding; functional genomics; glucose control; glucose disposal; glucose homeostasis; glucose regulation; glucose tolerance; glucose uptake; in vivo; insulin stimulated glucose disposal; lipoprotein disorder; metabolic abnormality assessment; nutrition; obese; obese people; obese person; obese population; ontogeny; personnel; phenome; ranpirnase; relational database; research study; square foot; transgenic
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
5P01DK049210-14_9004 (2009): $74579
Sponsored Links Excellgen http://Excellgen.com