“At the moment, we really don’t know the exact mechanisms that are causing ER stress in obesity and a high-fat diet,” Ozcan says. His team is now working to understand how the signals that result from ER stress make brain cells deaf to leptin, with the goal of developing drugs that derail the process more efficiently than the two drugs tested.
He believes that other scientists should begin investigating whether approved chemical chaperones could have the same benefit in humans. If so, this could lend support to the idea of using leptin as an obesity treatment in concert with a drug that helps the body utilize it. That has long been the hope of Amylin Pharmaceuticals, a company that has been conducting clinical trials of leptin in combination with a different kind of drug to increase leptin sensitivity.
Tamas Horvath, a neuroscientist at Yale University who also studies leptin in the brain, says that it makes sense for ER stress to be involved in leptin’s actions. Leptin levels rise with food intake, he explains, and ways to deal with incoming energy include building new structures or replace old ones. The ER is the primary site for new construction in the cell, so increased leptin signaling could lead to “overbuilding” and the ER eventually becoming overloaded if too many construction projects are initiated.
However, Horvath believes that blocking the natural response of ER stress and encouraging the cell to keep growing and producing is akin to creating a financial bubble: it will only lead to collapse. “Instead of interfering with ER stress, one should interfere with calorie intake,” he says. “This has been the only proven way so far to take care of health and longevity.”