11:30 - 11:35
Introduction
Jean-Pierre Montani
Department of Medicine / Physiology, University of Fribourg, Switzerland

The availability of genetically altered mice has brought considerable new ways to explore basic physiological functions. However, the small size of the mouse, the genetic background on which the mutants are generated, and the environmental conditions to which the mice are exposed have major repercussions on the phenotyping outcome. This will be illustrated in our symposium by the challenge of measuring blood pressure in mice (Bruce Van Vliet), the important role of the renin genetic background on the cardiovascular and renal phenotyping (Michel Burnier) and the limits in extrapolating metabolic and thermoregulatory findings from mice to humans (Abdul Dulloo). This symposium should emphasize that a careful characterization of the genetic background and a thorough understanding of the limits imposed by mouse phenotyping are all necessary to benefit from the development of genetically engineered animals.

11:35 - 12:00
Phenotyping mouse blood pressure: meaningful numbers and where to find them
Bruce N. Van Vliet
Division of Basic Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada

The availability of mice with highly targeted genetic alterations allows the control of blood pressure (BP) to be investigated at the level of individual genes and gene products. However, because a single gene may have only modest effects on BP, there is a great need for the blood pressure phenotype of these mice to be assessed as accurately and precisely as possible. This presentation will focus on approaches to phenotyping blood pressure in mice, comparing the strengths and weaknesses of available methods. Emphasis will be placed on the use of the telemetry method to avoid many of the potential pitfalls (e.g. restraint, recent anesthesia or surgery) associated with other methods. Additional topics to be covered include which indices best summarize the blood pressure phenotype, and the growing list of factors that may impact on blood pressure or its assessment in mice.

12:00 - 12:25
Role of renin genes in cardiovascular and renal mouse phenotyping
Michel Burnier
Division of Hypertension and Vascular Medicine, Lausanne, Switzerland

The development of genetically engineered animals in which genes are either over-expressed or disrupted has been associated with an increased use of mice in experimental research. Consequently, to investigate the complex phenotype of hypertension and cardiovascular diseases, the classical renovascular and mineralocorticoid models of experimental hypertension have been adapted from the rat to the mouse. Previous studies have shown that mice are polymorphic for the number of renin genes with some inbred strains harboring one gene, Ren-1c (e.g. C57BL6/J) whilst other strain contain two genes, Ren-1d and Ren-2 (e.g.129 strains). The Ren-1 genes express renin in the juxtaglomerular apparatus of the kidney whereas the Ren-2 gene controls renin mainly in the submaxillary gland and at very low levels in the kidney. The expression of Ren-2 in mouse submaxillary glands is on average 150 fold greater than Ren-1 in inbred strains. In several recent studies, we have investigated the impact of the renin gene background on the physiological response to salt and mineralocorticoids in mice. We found that the number of renin-gene is an important determinant of blood pressure and of the response to salt and DOCA in mice. Thus, a careful characterization of renin gene background should be performed whenever using mice to investigate the pathophysiology of hypertension and renal and cardiovascular diseases.

12:25 - 12:50
Phenotyping mouse for metabolic susceptibility to obesity: Magnification 2000X – a mouse-to-man dilemma
Abdul G. Dulloo
Department of Medicine / Physiology, University of Fribourg, Switzerland

After a decade of phenotyping mice that overexpress or lack gene(s) implicated in the control of thermogenesis and lipid metabolism, we have learned to expect the unexpected. In some cases, the failure to demonstrate the ‘expected’ can be pinpointed to a lack of appreciation that differences between mutants and wildtypes can only be unmasked by appropriate challenges, methodologies, and more robust numerical and statistical analysis of data. In other cases, the ‘unexpected’ has offered the opportunity to investigate compensatory or alternative mechanisms, and hence new models in the search for hitherto unexpected molecular pathways that might confer metabolic susceptibility to obesity. Equally important from lessons learnt during this past decade is the need to confront the issue of metabolic scaling and thermal regulation. How relevant are mice as a model for screening/revealing genes that might confer susceptibility to human obesity. Between a 30g mouse and a 60 kg human, there is a 2000-fold difference in body weight, and a 300-fold difference in metabolic body size (body weight¾). Mice are studied at laboratory temperature (22-24 °C), which is well below their zone of thermoneutrality (about 30°C), whereas humans live (and are studied) with their body kept in a microenvironment that is thermoneutral. The question therefore arises as to what extent the mechanisms underlying body weight homeostasis in mice, which are primarily driven by thermoregulatory needs, have relevance for weight regulation in humans. This issue will certainly gain greater importance with the expected exponential increase in number of candidate genes that mice phenotyping under standard laboratory conditions are likely to reveal over the coming years. There is therefore a need for more emphasis upon a top-to-bottom ‘systemic physiology’ approach for mouse phenotyping pertaining to the identification of genes that confer susceptibility to obesity in humans.