December 02, 2005
Leptin Restoration After Weight Loss Keeps Off Pounds

Leptin drops while people lose weight and that causes weight regain.

A team at New York's Columbia University has shown the key is falling levels of the hormone leptin, which controls appetite.

They found that giving people who had recently lost weight injections of the hormone helped them to avoid putting the pounds straight back on.

The study features in the Journal of Clinical Investigation.

Leptin is a peptide (i.e. it is a sequence of amino acids and peptides are what make up protein). Peptides taken orally get digested. So to use it you'd have to inject it with a syringe.

To test their theory, the researchers gave doses of leptin to lean and obese volunteers who had recently lost weight.

They found that most of the metabolic and hormonal changes which mean people cannot keep the weight from creeping back on were reversed once leptin levels were restored to pre-weight loss levels.

Leptin is known to play a role in controlling appetite, but as yet the exact way that it works is unclear.

Injections of leptin have been used to help morbidly obese people with a deficiency of the hormone to lose weight, but a similar approach has no effect on obese people with normal leptin levels.

So go on a diet. Lose weight. Then start taking leptin injections to keep the weight off.

Development of a method to increase leptin receptor concentrations on fat cells would also keep the weight off.

A new study by researchers at UT Southwestern Medical Center suggests that when fat cells increase in size – as they do during the development of obesity – the cells progressively lose receptors for the hormone leptin, a powerful stimulus for fat burning.

Leptin, a hormone produced by the body’s fat cells and involved in the regulation of body weight, was first discovered in 1994. It was thought leptin itself would be a key to curing obesity in humans, but the hypothesis did not readily translate into weight loss in obese people. Using mouse models, UT Southwestern researchers have now shown that if enough receptors are present on the fat cells, it is impossible for the cells to store fat and obesity would be blocked.

The new findings, appearing in an upcoming issue of the Proceedings of the National Academy of Sciences and currently available online, bring researchers a step closer to understanding obesity in humans, said Dr. Roger Unger, director of the Touchstone Diabetes Research Center at UT Southwestern and senior author of the study.

“We now think that people with naturally high levels of leptin receptors may not gain weight as rapidly over time as people who have low levels of leptin receptors,” said Dr. Unger. “It could explain why some people can eat more and do not gain weight.”

To test this hypothesis, the UT Southwestern researchers used genetically modified rats in which the leptin receptor remained present in large quantities even during marked overfeeding. In normal mice, the high-fat diet caused massive obesity with enlargement of fat cells to almost three times their normal size. In mice with the forced overexpression of the leptin receptor on their fat cells no obesity occurred, even though they too were fed high-fat, highly caloric diets.

“The fat-storing function of the fat cells requires the disappearance of the leptin receptor,” Dr. Unger said. “This is done in order to block the action of the leptin fat cells produce.”

Add the newly discovered peptide hormone obestatin to the injections and weight control becomes even more likkely.

Examination of the ghrelin gene showed Hsueh, Zhang and their colleagues that it in fact codes for a second peptide hormone — the hormone they named obestatin.

“Obestatin appears to act as an anorexic hormone,” said the Nov. 11 ‘Science’ article, “by decreasing food intake, gastric emptying activities, jejunal motility and body-weight gain.”

These observations led to the christening of the newly discovered hormone.

“On the basis of the bioinformatics prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rath stomach and named it obestatin — a contraction of obese, from the Latin ‘obedere,’ meaning to devour, and ‘statin,’ denoting suppression,” Hsueh said.

Also see my previous post Obestatin Hormone Suppresses Appetite.

We might be perhaps 10 or 15 years away from effective weight control treatments. Keep in mind that drugs normally take as long as 10 years to make it through the drug approval process. Some drug already it the pipeline might cure obesity. Or perhaps leptin could be sold for injections without a lengthy approval process. So it is hard to guess when obesity will become easily curable. But the knowledge about the mechanisms which cause obesity has advanced so much in the last few years that we now have sufficient scientific understanding on which to base development of obesity control therapies and appetite control therapies.

Share |      Randall Parker, 2005 December 02 07:04 AM  Brain Appetite

peter Andonian said at December 2, 2005 7:17 PM:

I find this topic very interesting and have been following it for a few years. There will be a great deal of money made by whoever gets a really effective drug out first, obviously. I would bet that the most effective avenue is going to involve blocking the insulin receptor on fat cells. Here is a referenece to a 2002 study with genetically engineered mice lacking an insulin receptor on their fat cells:
The mice stayed slim with no ill effects. The sucess of the Atkins approch is related to this mechanism, but if a drug can be found to block off this receptor selectively, It would be a vastly superior to any diet. There may even be positive heath effects beyond the normal ones of having lower body mass.

Rob said at December 3, 2005 7:31 PM:

Randall, check this out, IGF-1 levels correlate with cognitive ability. Wonder if we could mainline it.

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