Animal models for studying the genetic basis of metabolic regulation

Modern genetics has developed methods to modify the expression of genes 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 proteins in metabolic pathways, a new insight into the control of metabolism is 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 model is of particular value for promoter analysis because it is possible to introduce specific mutations into a putative regulatory region of a transgene and study its transcriptional control in the intact animal. Second, the developmental function of a gene product and its effect on various metabolic processes in a mouse can be directly determined by deleting a gene of interest by homologous recombination. Gene "knockout" mice are currently available with deletions in the genes for a variety of transcription factors and other biologically active proteins, permitting a critical analysis of the proteins responsible for the metabolic patterning of the animal. Third, the metabolic role of a gene of interest in a specific tissue can be studied by ablating its mRNA by the introduction of a transgene that codes for antisense mRNA targeted against the gene transcript. Because it is possible to use a transgene with a tissue-specific promoter, this procedure allows the isolation of the metabolic effect to a selected tissue in the transgenic animal. Taken together, these procedures provide a unique set of metabolic models for an in-depth study of metabolic regulation. This review will present examples of selected animal models currently available and will outline the challenge these animals present for investigators in the nutritional sciences.