Obesity drugs and their targets: correlation of mouse knockout phenotypes with drug effects in vivo

Abstract

Sequencing of the human genome has yielded thousands of potential drug targets. The difficulty now is in determining which targets have real therapeutic value and should be the focus of a drug discovery effort. The available evidence suggests that knockout technology can be used prospectively to identify targets that are amenable to drug development for the treatment of a variety of diseases. This review compares the knockout phenotypes of 21 potential obesity targets with the effects of therapeutics designed for those targets on rodents and, when data were available, on humans. The phenotypes of obesity target knockouts model the effects seen when therapeutics designed for those obesity targets are delivered to rodents; of the 21 obesity targets reviewed, 16 showed a correspondence between knockout phenotype and drug effect in mice and/or rats. This suggests that, at least in terms of evaluating obesity targets, it is rare for compensatory developmental changes caused by the gene knockout to prevent detection of the relevant phenotype. In the majority of cases, the knockout phenotypes also modelled the effects seen when the relevant therapeutics were delivered to humans. Thus, it seems rational to use mouse knockout technology prospectively to identify genes that regulate body fat in vivo, and then to develop anti-obesity therapeutics by targeting the human protein products of these genes. Ultimately, the value of using this approach to identify novel targets for human anti-obesity therapies will be judged by future studies examining the anti-obesity effect, in humans, of the therapeutics that result from this approach.

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

“…This observation supports the hypothesis that knockouts are useful for modeling the pharmacologic activity of agents that inhibit the action of specific proteins in vivo (18)(19)(20). Also, the Angptl4 Ϫ/Ϫ mice provided additional advantages in the study of Angptl4 physiology.…”

Differential modulatory effects of rosiglitazone and pioglitazone on white adipose tissue in db/db mice

“…Recently, several reports have been published comparing pioglitazone and rosiglitazone in an in vitro culture system (Guo et al 2006), in vivo animal models (Powell 2006) and human clinical trials (Beysen et al 2008;Goldberg et al 2005;Winkelmayer et al 2008). As a diabetic animal model, db/db mice were used in this study.…”

Cell basedin vitroandex vivomodels in metabolic disease drug discovery: nice to have or critical path?

“…In the 2005 update of the obesity gene map, there were 127 candidate genes with 426 reports showing their positive association with obesity [6]. Here, knock-out technology has shown its utility; out of 21 candidate genes, the knock-out phenotype mimicked the drug phenotype in 16 [7]. The current picture and future prospects for the pharmacotherapy of type 2 diabetes is much better.…”