Those of us with physical evidence of a few dietary indulgences might well be advised to climb some stairs and put a lock on the biscuit tin. But for the increasing number of people worldwide for whom excess weight is more than just an aesthetic problem, the most promising remedy will probably come as a pill that either curbs the appetite or prevents weight gain. By creating two mouse mutants that do not pile on the pounds, two groups now report progress towards producing such a wonder drug.

The first study started with a lean mutant mouse. Animals in which C/ebpα , one of several genes required for the differentiation of fat cells, is replaced with another such gene, C/ebpβ , are leaner and live longer than wild-type littermates. Chih-Hsien Chiu and colleagues show that these so-called β/β mice do not put on weight: when they were put on a fatty diet they gained no more weight than mice on a normal diet, even though they ate almost 20% more. The explanation for this desirable physiology lies in changes in the behaviour of white adipose tissue (WAT), which switches from storing energy to burning it. The number of active mitochondria is increased in β/β WAT, probably due to increased levels of the G protein α stimulatory protein (Gαs) in WAT; this hypothesis, which was based on gene expresssion levels, was confirmed when overexpression of Gαs led to the production of new mitchondria in fat-laden cells in culture.

A second study looked at another aspect of defects in regulating energy balance. By placing stress on the body, obesity leads to several health problems, one of which is the development of insulin-resistant (type 2) diabetes. Mouse studies have highlighted the activation of the JNK signalling pathway in obesity and insulin resistance, and Anja Jaeschke and co-workers have looked into this in more detail. To obviate the pleiotropic effects of removing JNK itself, the authors have analysed mice that are mutant for Jip1 , which encodes a scaffolding protein downstream in this pathway. Like the β/β mice, Jip1−/− animals didn't gain weight when put on a high-fat diet; in addition, they showed increased insulin sensitivity in adipose tissue. Jip1 deficiency therefore protects mice against obesity and insulin resistance. The way it does so is by reducing the activation of the JNK pathway in fat and muscle in response to high food intake, which in turn increases an inhibitory signal to the insulin pathway.

Harnessing the weight-busting power of Gαs and of Jip1 mutants is what dreams are made of. But are they too good to be true? JIP1 is a candidate gene for type 2 diabetes in humans, so the prospects of transposing the studies from mouse to man — leading ultimately to drugs that block JIP1 — look promising. The therapeutic value of understanding the phenotype of the β/β mouse was also emphasized by the observation that the β/β knock-in alleles are able to mitigate the obese phenotypes of two mouse models, Lep ob and Cpe fat , which gain weight through excessive eating or lowered metabolism, respectively. The two studies combined therefore put us in good stead to counter both environmental and hereditary causes of obesity, and its damaging consequences on health.