Animal models with altered genetic expression - The Genetics of Human Obesity

Transgenic techniques involve introduction of genes (or regulatory sequences) into the germline of mice so that target gene expression may be either introduced de novo or alternatively up or downregulated whereas knockout techniques involve elimination of endogenous gene expression. These genetic manipulations have provided a powerful tool for the study of gene function in the intact animal but have led in some instances to the publication of confusing or unexpected results.

Thus, animals lacking dopamine β-hydroxylase are completely unable to synthesize catecholamines but do not develop obesity (Thomas and Palmiter, 1997). Also, animals carrying a knock-out version of the Y5 form of the NPY receptor are phenotypically normal until they develop a late onset form of obesity due to overfeeding rather than the underfeeding which might be expected from the known physiology of this receptor system (Erickson et al., 1996; Palmiter et al., 1998).

Another problem is the fact that some germ line mutations are incompatible with foetal development and, with rare exceptions such as the intrauterine rescue of dopamine β-hydroxylase knockout mice with temporary provision of a downstream metabolite (Thomas and Palmiter, 1997), it has not been possible to produce an adult animal model of such mutations.

It is likely that recent refinements of these techniques to permit both temporal activation/de-activation of the gene, and tissue specific modulation of gene activity will greatly enhance the usefulness of this research tool.

Thus inserted or wild-type gene expression may be linked to a tissue specific promoter or to an inducible regulatory sequence (e.g. a tetracycline response element) so that, in this case, gene expression is either enabled or inhibited by the presence or absence of tetracycline in the animal's blood.

However, even with advanced conditional (as opposed to classical germ line) gene expression targeting, there still remain problems of interpretation caused by factors such as the redundancy evident in the control of energy homeostasis leading to compensation for the failure of one regulatory component by up-regulation of another.

Warden CH and Fisler JS
Katsanis N, Beales PL, Woods MO