THE ROLE OF LEPTIN GENE IN OBESITY

The role of Leptin Gene in obesity



The role of Leptin Gene in obesity

Leptin

Leptin (the satiation hormone) controls food intake in rodents. The Donny Strosberg-Tarik Issad team (CNRS molecular immuno-pharmacology laboratory at the Institut Cochin de Génétique Moléculaire in Paris), in collaboration with that of Metin Ozata (Department of endocrinology and metabolism at the Gulhane School of Medicine, Ankara) has recently found a mutation in the leptin gene in a closely inbred family. (Ahima and J.S. Flier, 2000)

These results, which confirm the role of leptin in obesity and hormone function in humans, were published in an article in the March 2, 1998 issue of Nature Genetics. Due to this mutation, three members of this family (2 adults and 1 child) do not produce normal leptin and are extremely obese. The two adults also show sexual immaturity, a fact which illustrates for the first time that this hormone, produced by adipose tissue, also controls the development of the reproductive function in humans. Leptin, a hormone produced by adipose tissue, was first discovered in mice. It plays a key role in the regulation of weight increase: when adipose mass increases, the leptin secreted by adipose tissue reduces appetite and increases energy expenditure by acting on the brain, thus preventing weight increase. Certain mice (ob mice) carry a mutation making them totally deficient in leptin. These mice are extremely obese, have an enormous appetite, and show a certain number of hormonal and metabolic disorders, such as diabetes. One of the major characteristics of these animals is their infertility, linked with sexual immaturity (absence of puberty). These disorders can be corrected by a treatment using synthetic leptin: the food intake of the treated mice decreases, they lose weight and become fertile. (Ahima and J.S. Flier, 2000)

In humans, the first research in leptin gene mutations gave no results. Most obese humans show no leptin deficiency; on the contrary, their leptin levels in the blood are usually quite high. The ob gene encoding mouse leptin was cloned in 1994 . Subsequently, leptin was identified as an adipocyte-derived hormone that circulates in the blood in proportion to whole body adipose tissue mass. Leptin is a key afferent signal linking adiposity level and nutritional status to neuroendocrine regulation of energy homeostasis mainly through reduction in caloric intake and enhancement in energy expenditure. Administration of leptin to young, lean rodents produces dramatic fat and weight loss. Additionally, leptin replacement in obese ob/ob mice corrects metabolic defects and ameliorates obesity and . However, in rodent and human models of diet-induced or adult-onset obesity, even though leptin levels rise proportionally with adiposity, the increased leptin fails to curtail the progression of obesity and . Moreover, obese humans and rodents are weakly responsive or unresponsive to exogenously administered leptin . This apparent leptin ineffectiveness is identified as leptin resistance. Despite extensive research efforts, the nature of this resistance is yet to be fully delineated. (Ahima and J.S. Flier, 2000)

leptin recepter

While the hormone leptin and its receptor were ...