ONE of the horrors of obesity is that once it takes hold it is fiendishly difficult to reverse. The overweight often find it impossible to avoid eating to excess, and so the kilos continue to pile on. Judgmental observers of this pattern might simply blame lack of willpower—and it is certainly true that willpower in prodigious quantities is needed to climb back up the slope to svelteness. But understanding why that slope is so slippery might help the sinner who wishes to repent, and such understanding may have come a little closer this week with the publication in Cell Metabolism of a study by Jens Brüning, of the Max Planck Institute for Neurological Research in Cologne, and his colleagues.

Obesity is one manifestation of a group of symptoms known as metabolic syndrome. Another symptom is late-onset diabetes. Unlike its cousin early-onset diabetes, which is caused by a lack of insulin, the late-onset variety results from resistance, in those cells that should react to the hormone, to insulin that is in fact available. This has all sorts of bad effects, since insulin regulates the absorption and release of sugar and, though late-onset diabetes is not quite the killer that the early-onset variety is, the result is still pretty nasty.

Dr Brüning found himself wondering if such resistance extended to insulin-regulated cells in the brain, and whether that might be an explanation for the inappropriate appetites of the obese. To find out, he looked at the behaviour of such cells in the part of the midbrain responsible for producing the sensation of pleasure.

Genetic technology allows genes, and thus the proteins those genes encode, to be knocked out of individual mice. Dr Brüning knocked out the insulin-receptor gene that is expressed in midbrain cells. Specifically, the cells in question were the ones responsible for making the precursors of dopamine, a signalling molecule with a well-established role in generating the sensation of pleasure. He tested cells from both sorts of mice to make sure that those with the receptor gene knocked out really were less active than the others in the presence of insulin (they were) and then monitored the feeding patterns of the two types of mice.

The upshot was that the knockout mice ate considerably more than the normal animals. At six weeks of age, the onset of adulthood, the average meal size of a male mouse whose insulin-reception system had been damaged was 3.2 grams of rodent chow. A male whose insulin receptors were normal ate 2.8 grams. Females showed a similar pattern, eating 3.1 and 2.7 grams respectively. And this increased food intake did, indeed, lead to obesity. The bodies of adult knockout males were 23% fat. Those of the control males were only 18% fat. (Corresponding figures for females were 12% and 10%, since females are the slimmer sex in mice.)

By themselves, these results do not prove that insulin-resistance is the explanation for the tendency of the already-lardy to eat too much. Mice are not men (though the similarity is closer than many would like to think), and a genetic knockout is not the same as naturally acquired insulin resistance. Moreover, as sharp-eyed readers will have noticed, there is something odd about a mechanism that increases the appetite by reducing the production of a chemical which causes the sensation of pleasure. Clearly, a lot more work is needed to unpick the details. But if Dr Brüning is on the right track, the slippery slope that leads to obesity may eventually get a little easier to climb back up.