Pre-Existing Drugs May Restore Sensitivity to Leptin, an Appetite Suppressing Hormone

Hearts in the medical community beat with considerable excitement at the discovery of leptin in 1994. A hormone produced by fat, leptin has a very useful talent: it tells the brain when to stop eating. So hopes were high that leptin would become the basis of an anti-obesity treatment. What could be simpler than to dose an obese person with a hormone that says, “You’re not hungry any more, and you want to stop eating.”

Unfortunately, a snag soon emerged. Obese people do not respond to leptin. Scientists faced two mysteries: First, how do people become resistant to leptin in the first place? And second, are there any drugs that increase sensitivity to leptin?

Those questions have remained unanswered for a long time. But a Children’s Hospital Boston study, published in the January 7 issue of Cell Metabolism, may have found the answers to both.

First, it appears that a stress-induced condition causes the hypothalamus, the region of the brain that responds to leptin, to resist the hormone.

Second, two drugs (4-PBA and TUDCA), which are already approved by the FDA for use in other medical applications, appear to greatly increase leptin sensitivity. The receptivity of lab mice resistant to the hormone increased as much as 10-fold when the two drugs were used as “chemical chaperones” to prime the mice for leptin injections.

The Boston study found that a condition called “endoplasmic reticulum” stress in the body’s peripheral organs leads to leptin resistance. The endoplasmic reticulum (ER) is a cellular component that produces proteins. Other cellular components, called “molecular chaperones,” then fold the protein into its ultimate three-dimensional shape and transport it. When the chaperones can’t keep up, a stress response is triggered, called “unfolded protein response” (UPR).

The researchers suspected that ER stress and UPR blocked leptin’s action in the brain and were at fault for the hypothalamus’s leptin resistance. Previous studies had already shown that mice bred to have ER stress were leptin-resistant and tended to obesity. Once the researchers ascertained that such was the case, they turned to an experimental drug therapy that involved using 4-PBA and TUDCA as chemical chaperones.

Currently, 4-PBA (buphenyl) is used to treat cystic fibrosis and urea cycle disorders, while TUDCA (tauroursodeoxycholic acid) is used to treat liver diseases. Both are also being studied for possible treatment of Alzheimer’s and Huntington’s diseases. Because both drugs are already FDA-approved, the researchers believe that it will be easy to move them quickly to human trials.

A side benefit of the drugs’ role as chemical chaperones is that they have also been shown to reduce ER stress in mice with type 2, restoring insulin sensitivity and normalizing blood sugar levels.

Besides being a safe treatment for increasing leptin sensitivity in obese people, the drugs could also enter the rapidly expanding pharmacopeia of diabetes treatment medicines.

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