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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: bluejeans who wrote (17886)	3/25/1998 10:44:00 PM
From: Henry Niman	Respond to of 32384

Speaking of tomorrow's news today, tomorrow's Nature has an article of interest to LGND shareholders (and it's already linked to LGND via Bloomberg): A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here the authors describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans. K Cl‚ment, C Vaisse, N Lahlou, S Cabrol, V Pelloux, D Cassuto, M Gourmelen, C Dina, J Chambaz, J-M Lacorte, A Basdevant, P BougnŠres, Y Lebouc, P Froguel & B Guy-Grand A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction (Letters to Nature) Nature 392, 398 (1998)

To: bluejeans who wrote (17886)	3/25/1998 10:48:00 PM
From: Henry Niman	Respond to of 32384

Here's the News & Views view of Life without Leptin: News and Views. HUMAN PHYSIOLOGY Leptin is known to be involved in the control of body fat, but does it have any other functions? Two studies of human families with disrupted leptin function - one through mutations in the leptin receptor and one through mutations in leptin itself - indicate that the answer is 'yes'. As well as being morbidly obese, young adults in both families have impaired reproductive function and they do not seem to have gone through puberty. Stephen O'Rahilly Life without leptin Nature 392, 330-331 (1998

To: bluejeans who wrote (17886)	3/25/1998 11:01:00 PM
From: Henry Niman	Respond to of 32384

Here's a fairly recent report on leptin (like insulin?) resistance: 02/02/98- Updated 12:29 PM ET Leptin hormone doesn't suppress appetite A new study casts doubt on a theory that leptin, a hormone produced by fat cells, might be useful in treating obesity. It has been known that fat mice, like fat humans, have high levels of leptin, while thin mice and thin humans have low levels. Very low levels cause animals to eat voraciously and to process food very efficiently, says Bruce Boston of Oregon Health Sciences University, lead author of a paper in today's Science. Since low levels of leptin stimulate appetite, he says, researchers thought the converse would be true: "The idea was high levels of leptin would reduce feeding and make inefficient metabolism," he says. But Boston's findings indicate "it doesn't seem to do that," he says. In fact, he says, the obese mice in his study didn't change their eating habits when given leptin and appeared to have developed a tolerance for it. "An already high level probably desensitizes the animal to even higher levels," he says. "It's unlikely higher levels of leptin will work" to turn off the appetite, as hoped. The findings suggest that the evolutionary purpose of a shortage of leptin is to prompt a starvation response in times of scarce food, causing the body to eat more and to burn calories slowly, Boston says. But there does not appear to be a converse appetite shut-off mechanism in times of abundance. "This is bad news because people were hoping leptin would be a positive thing," Boston says. "But the more we understand about how leptin works in the brain, the better we're going to be able to design drug targets that will be effective." By Anita Manning, USA TODAY

To: bluejeans who wrote (17886)	3/25/1998 11:19:00 PM
From: Henry Niman	Respond to of 32384

Here's the Reuter's version of the paper: Wednesday March 25 6:39 PM EST Genetic Basis Found For Severe Obesity NEW YORK (Reuters) -- A team of French researchers has discovered a genetic defect that can lead to extreme obesity and failure to enter puberty. The defect interferes with the body's ability to respond to leptin, a hormone that regulates appetite and energy expenditure, according to the report in the March 26th issue of the journal Nature. Dr. Philippe Froguel, of the Institut Pasteur, Lille, France, and colleagues studied a family in which three sisters became severely obese within the first months of life, despite normal birthweight. The girls did not develop breasts or underarm hair, and, at ages 13.5 and 19, two of them had not menstruated. One sister died at age 19 without having menstruated. The researchers found that blood levels of leptin were twice as high in the severely obese sisters as in their parents and three of their siblings. Therefore, they decided to study the leptin receptor gene in this family. The leptin receptor is a protein that binds to leptin and influences how leptin is used by body cells. Froguel's team discovered that the three sisters had two copies of a mutation in the leptin receptor gene. As a result, the leptin receptor in these girls does not function properly, according to the research team's report. The other family members either did not have the mutation or had only one copy. In addition to regulating appetite and energy expenditure, leptin must also regulate body weight, growth and sexual maturation, Froguel and his colleagues conclude. The three sisters showed decreased levels of several hormones that help regulate growth and metabolism. "These results indicate that leptin is an important physiological regulator of several endocrine (hormonal) functions in humans," Froguel's group concludes. "The growing evidence that humans can be genetically hardwired to become severely obese should eventually lead to a more widespread realization that morbid obesity is a disease requiring further scientific research," Dr. Stephen O'Rahilly, of the University of Cambridge, UK, comments in an accompanying editorial, "rather than a failure of will-power requiring sanctimonious moral opprobrium." SOURCE: Nature (1998;392:330-331, 398-401)