A new study in the January 7th issue of Cell Metabolism, a Cell Press publication, helps to explain why obese people and animals fail to respond to leptin, a hormone produced by fat that signals the brain to stop eating. What's more, they show that two FDA-approved drugs might restore leptin sensitivity, offering a novel treatment for obesity.
" Most importantly, our study is the first success in sensitizing obese mice on a high-fat diet to leptin," said Umut Ozcan of Harvard Medical School. "If it works in humans, it could treat obesity."
When leptin was first discovered some 13 years ago, it led to great excitement in the field, Ozcan said. Studies showed that leptin administered to obese mice that lacked the hormone lost weight. The buzz over leptin's potential as an obesity therapy soon waned, however, because obese animals and people don't respond to the hormone. Efforts to find drugs that act as leptin sensitizers over the years have also failed.
A part of cells known as the endoplasmic reticulum (ER) is involved in many cellular processes including protein manufacturing, lipid and carbohydrate synthesis, and other functions. Stress in the ER appears to play a role in a metabolic disorder linked to obesity. These researchers decided that perhaps ER stress played a role in reduced response of the brain's hypothalamus to leptin.
Recent studies by him and his colleagues showed that a condition known as endoplasmic reticulum (ER) stress in peripheral organs plays an important role in obesity-induced insulin resistance and type 2 diabetes. Ozcan describes ERs as protein factories within cells. Within those cellular components, molecular chaperones, which serve as the factory workers, facilitate the folding and transport of proteins. When the chaperones can't keep up, it triggers a stress response known as the unfolded protein response (UPR).
The researchers went looking for drugs that could reduce ER stress in hopes that ER stress reduction would make the hypothalamus more sensitive to leptin and thereby reduce appetite. Turns out, ER stress reduction caused mouse weight loss.
The question then became whether the animals could be resensitized by treating them with either of two pre-existing drugs (4-Phenyl Butyric Acid [PBA] and Tauroursodeoxycholic acid [TUDCA]) that act as ER stress reducers. And the answer, they report, is yes.
" It was very exciting," Ozcan said of the discovery. "Normal mice treated with the drugs dropped some weight and quickly rebounded, but the knockout mice [that were genetically predisposed to ER stress in the brain] continued to lose weight. It shows that ER stress relievers are leptin sensitizers."
This research does not prove that ER stress reducer drugs will reduce appetite in overweight humans. Also, ER stress reduction in humans might turn out to be very difficult to do without undesirable side effects. Development of drugs which have only very specific effects is usually a difficult and problematic undertaking.
ER stress probably increases with age as cells malfunction due to accumulated damage. So rejuvenation therapies will probably, as a side effect, make us skinnier. But this study underlines the need to rejuvenate the brain - which is by far the most difficult organ in the body to rejuvenate.
|Share |||Randall Parker, 2009 January 24 10:04 AM Brain Appetite|