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Genetic Studies to Overcome Leptin Resistance

written by: •edited by: Paul Arnold•updated: 6/22/2010

Leptin is a hormone that regulates appetite. It signals the brain telling it that we've had enough to eat. Nearly all obese people are resistant to leptin, which makes losing weight difficult. Genetic studies may provide new drugs to overcome leptin resistance and help people lose weight.

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    Causes of Obesity

    Variation in body fat 12577 The obesity pandemic engulfs much of the world as waistlines expand and health systems are bursting at the seams trying to cope with the fall out. The causes of obesity have been drummed into us time and again through public health messages and newspaper, magazine, and television reports and they include low self esteem, sedentary lifestyle, and eating too much of the wrong kinds of foods. Further causes could be biological; genes for obesity have been suggested and then there is the fact that many obese people are resistant to the appetite regulator leptin.

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    What is Leptin?

    Leptin is a hormone that is produced by adipose tissues and its roles include exerting an influence over food intake and energy expenditure. When we feel that we have had enough to eat, leptin signals the brain to tell the body that we are full. This fact lead to studies that administered leptin to obese subjects with the hope that it would help them to lose weight. If the brain could be fooled into thinking that enough had been eaten then appetites would shrink. Well that was the prevailing thought, however, the results were far from successful, with only minimal weight being lost.

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    Leptin Resistance

    It turns out that there is plenty of leptin in the fat cells of obese people; in fact in some obese individuals the level is unusually high which must mean that in these people the hormone is not functioning properly. This has been termed leptin resistance, and could be why some people just keep on eating.

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    Overcome Leptin Resistance

    Molecular and genetic studies are offering a number of potential therapeutic targets to overcome leptin resistance.

    In 2002 scientists at the Beth Israel Deaconess Medical Center (BIDMC) created knockout mice that lacked a gene that coded for a protein called PTP1B (protein tyrosine phosphatase 1B).They observed that these mice were exceptionally lean, even when fed a high fat diet. In addition mice energy expenditure increased. The authors speculated that the protein regulates the leptin signalling pathway and suggested the possibility that drugs could be designed to silence the proteins, which could result in weight loss in humans.

    Leptin sends its 'stop eating signal' to the brain after it is released from fat cells. The hypothalamus 'reads' the amount of leptin circulating in the blood and adjusts the body's response accordingly i.e. to regulate appetite or metabolism.

    Leptin binds to receptors on various types of nerve cells including POMC neurons, and this activates other cellular signals . Studies from leptin resistant mouse models have shown that when leptin receptor activity is restored in just the POMC neurons the animals consume 30% fewer calories, are a little more active, and lose a modest amount of weight.

    In 2006 researchers at the Albert Einstein College of Medicine of Yeshiva University found that one of the cellular signals released after leptin-receptor binding is a molecule called STAT3 and that it is essential for reducing food intake.

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    The more that is known about the molecular biology of leptin and how leptin resistance leads to obesity, the better our chances of intervening in the molecular pathways to influence weight loss. For example, a drug could be designed that could bypass leptin completely to interact directly with STAT3 to normalize an obese individual's appetite. However, it may be some time before a 'magic pill' is available on the market, and in any case doctors advise that the best ways of tackling obesity are with lifestyle and dietary adjustments.

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    Photo Credit

    Walter Siegmund - released under GNU Free Documentation License