Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C05 and PC05
A conditional knock-out mouse model for XLαs; a signalling protein involved in the suppression of metabolic rate and energy expenditure.
S. O. Krechowec1, A. Plagge1
1. Physiological Laboratories, University of Liverpool, Liverpool, United Kingdom.
The regulation of energy homeostasis and an organism’s subsequent adiposity and body weight is controlled by a highly complex system of neural, endocrine and metabolic processes which have only recently begun to be identified. With the current epidemic in human obesity, research has focused upon how the dysregulation of these inter-connected physiological processes can cause obesity and on identifying pathways that prevent or reverse obesity development. The development of animal models provides essential tools for investigating the complex systems involved in regulating energy homeostasis; one unique model is the XLαs knock-out mouse. XLαs (eXtra Large αs) is an NH2-extended variant of the ‘a-stimulatory’ subunit of the trimeric G-protein, Gαs, one of three proteins encoded by the complex imprinted Gnas locus. At birth knock-out mice display poor feeding, increased neonatal mortality and very limited adipose development, while adult survivors go on to develop a healthy exceptionally lean, insulin-sensitive, hypermetabolic phenotype, weighing ~45% lighter with less than half the body fat of wild-type controls and showing increased sympathetic tone. This knockout provides one of the few lean mouse models and represents a valuable tool that can be used to identify novel pathways involved in obesity prevention or treatment. Given the highly complex phenotypes generated by global gene knockouts a more refined conditional approach is necessary to precisely identify the mechanisms arising from the temporal, tissue and cell-specific effects of Gnasxl (XLαs) deletion. In this study we describe the development of a novel, conditionally targeted Gnasxl mouse model. In order not to interfere with the complex regulatory mechanisms of the imprinted Gnas locus, we designed a conditional gene-trap approach. Tissue-specific Cre expression causes an inversion of the gene-trap cassette, resulting in truncation of XLαs and the formation of a lacZ fusion protein. This conditional Gnasxl knock-out provides the tool necessary to dissect the individual tissue-specific mechanisms that contribute to the lean and hypermetabolic phenotype exhibited by global Gnasxl knock-out mice. Progress in the analysis of brain-specific XLαs deletions will be presented.
Where applicable, experiments conform with Society ethical requirements