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to the DERC Website: Physiology Core
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Physiology Core |
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Allen Clermont Assistant Core Director
Nahtlin Guarnieri Lab Manager
Rodent Models:
1. Energy Homeostasis: Feeding behavior, body composition, oxygen consumption and activity monitoring.
2. Vascular Studies: Blood pressure measurements by tail blood pressure cuffs and by telemetry.
Background:
Diabetes and obesity represent significant health problems (1-6). Research over the past two decades has increased our understanding of the molecular mechanisms contributing to the development of these pathologies and their complications. Much of this work utilized animal models for understanding basic mechanisms that could then applied to human disease. One naturally occurring animal model that has been extensively studied is the ob/ob mouse. This animal was originally found to be massively obese and insulin resistant. Identification of the genetic defect of the ob/ob mouse by Friedman (5) led to the discovery of leptin and to an understanding of the role of fat in the regulation of energy homeostasis. The relevance of this finding to human obesity is significant, in that humans with mutations in either leptin (6) or the leptin receptor (7) have a phenotype that mimics that of the ob/ob mouse.
Similarly, the importance of the melanocortin pathway for energy homeostasis derived from analysis of spontaneously occurring models of mouse obesity. Analysis of the agouti mouse revealed that disruption of the melanocortin pathway leads to obesity (8), a finding that was confirmed by generation of a melanocortin 4 receptor knockout mouse (9). Subsequently, melanocortin 4 receptor mutations were associated with human obesity (10,11), and further research suggests that signaling defects in the melanocortin 4 receptor may account for as much as 4% of severe early onset human obesity. In addition, human obesity has been associated with mutations in the POMC gene (12).
Specific animal models have been developed in order to understand the physiology of human type 2 diabetes, as the spontaneously occurring models differed significantly from the human disease, which features hyperinsulinemia, insulin resistance and islet cell failure. For example, one genetically engineered mouse represents a polygenic model of type 2 diabetes as these animals are insulin resistant and hyperinsulinemic (13). To understand the nature of insulin resistance in type 2 diabetes additional research is being focused on a number of models in which the insulin receptor is ablated in a single tissue (in the Kahn laboratory, models include adipose, muscle, brain, liver and beta cell targeted knockouts) (14). Other groups have used knockout mice to study additional molecules important in insulin signaling pathways, for example GRP-1 in the Czech laboratory (15) and PTB1-B in the Neel laboratory (16).
Genetically engineered mice may have a predicted or unexpected phenotype. While ablation of the orexigenic neuropeptide MCH leads to a lean phenotype (17), NPY ablated mice have a normal feeding phenotype (18), although they appear to have a decreased seizure threshold and increased preference for alcohol (18,19). Hence, the analysis of such mice may involve complex physiologic and behavior studies. All such studies require significant expertise. While the protocol of an intraperitoneal glucose tolerance is simple, the individual handling the mice must be experienced in rapidly and effectively obtaining blood samples, as even minimal stress will raise mouse blood glucose. Other analyses, such as monitoring of VO2 require expensive equipment.
Vascular complications are the major cause of morbidity and mortality of diabetes and insulin resistant states. Dr. George L. King's laboratory has focused its efforts on the role of Protein Kinase C and other kinases on the development of diabetic microvascular and cardiovascular complications. The King laboratory has made several targeted PKC beta isoform transgenic mice, overexpressing this in the myocardium or blood vessels, which has led to the production of multiple phenotypes including hypertension, cardiac hypertrophy and macroaneurysms. Analysis of vascular function may also be difficult. A measurement as basic as blood pressure monitoring in mice requires both relatively expensive equipment and a high level of expertise. Blood pressure can be measured either using radiotransmitters and telemetry or use of high fidelity transducers, both of which require investment in equipment and training of personnel in technically complex procedures.
These requirements may make it difficult or impossible for a single laboratory to establish a particular procedure locally; this is particularly true for procedures that are procedure intensive or which require expensive specialized equipment. In addition, when a genetic manipulation produces an unexpected phenotype involving diabetes or obesity, the laboratory that generated the mice may not be familiar with even more basic techniques for analyzing the appropriate parameters. Hence availability of a centralized facility offering both basic and complex services would facilitate understanding of the molecular basis of both disorders of energy and glucose homeostasis. Such a centralized facility can offer expertise intensive procedures, such as equipment-dependent procedures, VO2 measurements, and more basic services such as glucose tolerance testing and insulin tolerance testing.
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