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The discovery of leptin in 1995 made headlines worldwide. When obese mice were injected with this appetite-suppressing hormone, they ate less and lost weight. Amgen, Inc. paid $20 million for commercial rights to the drug, a record at that time. But hopes that leptin could cure human obesity faded when it was found that obese people develop leptin resistance. "Leptin goes to the brain and knocks on the door, but inside, the person is deaf," says researcher Umut Ozcan, MD, in Children's Hospital Boston's Division of Endocrinology.
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Metabolism, Ozcan and colleagues explain why this happens, and report that two existing drugs can restore the brain's sensitivity to leptin. First, they showed that the brain cells of obese mice have increased stress in the endoplasmic reticulum (ER)—the place where proteins are assembled, folded and dispatched to do jobs for the cell. When mice were made obese through a high-fat diet, the overstressed ER sounded an alarm—triggering a response that ultimately blocked leptin's action. When Ozcan's team created a strain of mice whose ER was weakened in brain cells, results were the same: ER stress and leptin resistance developed, causing the mice to eat more and gain more weight.
But when either group of mice was pretreated with the compounds 4-PBA and TUDCA, which relieve ER stress, leptin sensitivity increased as much as 10-fold, and the mice had significant weight loss with leptin treatment even when fed a high-fat diet. "I think our study will bring new hope for the treatment for obesity," Ozcan says.
He's not the only one to think so. David Ludwig, MD, PhD, director of Children's Obesity Program, is seeking funding for a clinical trial of 4-PBA and TUDCA—both already FDA-approved for other uses—in humans with obesity.
Lale Ozcan, MD, also of Endocrinology, was the first author of the paper; co-authors included Ayse Ergin, MD, Allen Lu, Jason Chung, PhD, and Sumit Sarkar, PhD, from the Ozcan lab and Duyu Nie, PhD, of Neurobiology.
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