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Animal Models for Studying the Genetic Basis of Metabolic Regulation^1,2,

Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-3649 ^* Department of Pathology, Baylor Medical College, Houston, TX

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.

KEY WORDS: • homologous recombination • antisense RNA • transgenic animals • gene transcription • metabolic pathways

¹ Supported by grants DK 21859 and DK24451 (to R.W.H.) and by the Metabolism Training Program grant DK 07319 (to S. E. N., P. S. L and C. M. C.) from the National Institutes of Health.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ Winner of the 1995 Osborne and Mendel Award from the American Institute of Nutrition. This review describes the research in the area in which the recipient was acknowledged for his contributions to nutritional science.

⁴ To whom correspondence should be addressed.

Manuscript received 8 February 1996. Revision accepted 10 June 1996.

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