ANIMAL-MODELS FOR STUDYING THE GENETIC-BASIS OF METABOLIC-REGULATION

Modern genetics has developed methods to modify the. expression of gen es in animals to study the factors responsible for the tissue-specific expression and hormonal and dietary regulation of metabolic processes . As these methods are applied to genes that code for critical protein s in metabolic pathways,a new insight into the control of metabolism i s emerging. There are three general approaches currently in use. First , is the introduction of genes into the germ line to create transgenic animal models in which the gene of interest is over-expressed. This m odel is of particular value for promoter analysis because it is possib le to introduce specific mutations into a putative regulatory region o f a transgene and study its transcriptional control in the intact anim al. Second, the developmental function of a gene product and its effec t on various metabolic processes in a mouse can be directly determined by deleting a gene of interest by homologous recombination. Gene ''kn ockout'' mice are currently available with deletions in the genes for a variety of transcription factors and other biologically active prote ins, permitting a critical analysis of the proteins responsible for th e metabolic patterning of the animal. Third, the metabolic role of a g ene of interest in a specific tissue can be studied by ablating its mR NA by the introduction of a transgene that codes for antisense mRNA ta rgeted against the gene transcript. Because it is possible to use a tr ansgene with a tissue-specific promoter, this procedure allows the iso lation of the metabolic effect to a selected tissue in the transgenic animal. Taken together, these procedures provide a unique set of metab olic models for an in-depth study of metabolic regulation. This review will present examples of selected animal models currently available a nd will outline the challenge these animals present for investigators in the nutritional sciences.