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.
However, the underlying reason why obese individuals become leptin resistant in the first place remained open to question. The new study by Ozcan's team has shed some light on that issue.
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).
Ozcan suspected that ER stress and the UPR response might also lead to leptin resistance in the brain's hypothalamus. The hypothalamus is the primary brain region that responds to leptin, sending a signal that curbs appetite. Mice engineered to have reduced ER capacity or increased ER stress throughout their bodies do gain more weight on a high-fat diet, according to earlier studies.
Ozcan now reports that obese mice manipulated to have increased ER stress only in the hypothalamus show less response to leptin. The animals are not only more leptin resistant, but they also grow significantly more obese on a high-fat diet.
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."
That makes PBA and TUDCA the first leptin sensitizers, Ozcan emphasized.
" A leptin-sensitizing agent has not been previously described despite the long-standing efforts in both academia and industry," he wrote. "The results presented in this study provide evidence that chemical chaperones, particularly the PBA and TUDCA, can be used as leptin-sensitizing agents. When the high safety profiles of PBA, TUDCA, and leptin are taken into consideration, our results may define a novel treatment option for obesity."