Another Clue to the Riddle of Obesity

New research at the Institute sheds some light on a protein that could make it harder for overweight people to stick to a diet.

That protein helps regulate the effects of leptin - a hormone that reduces appetite and increases physical activity. People missing the leptin gene are invariably obese. It turns out, however, that this mutation is extremely rare; in fact, most chronically overweight people have too much leptin rather than too little. This happens because the body develops resistance to the hormone, so it amps up the signal, trying to be heard. It's also an indication that simply injecting leptin won't do much for one's weight.

How does the body learn to ignore leptin? The Weizmann scientists found that the protein they were investigating regulates leptin signals in an area of the brain called the hypothalamus. This protein responds directly to leptin, and dampens its signal. In normal, obese mice this leads to leptin resistance, but mice lacking the protein remain sensitive to the hormone's effects.

At least in women. The scientists originally carried out the study in female mice that were genetically engineered to lack the protein. At first they were searching for a link between the protein and bone health, and they had also removed the mice's ovaries to simulate osteoporosis. But then they noted that the "menopausal" lab mice, which normally would have been adding something like 30% to their body weight, were looking unusually trim and healthy. The researchers started feeding the mice high-fat diets, looking for the explanation. They later tried the experiment in male mice - engineering them to lack the protein and then feeding them high-fat diets. Sadly enough for the males of the species, the benefits were practically non-existent.

So, on the one hand, this study highlights just how complex is the pathway that leads to obesity. It implies that men and women might regulate hunger and satiety in different ways, and that resetting our body mass could be a complicated undertaking. On the glass-half-full side, however, if someone can figure out how to safely block that protein in the hypothalamus, there might be some small ray of hope for treating obesity in the future, after all.


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