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Tuesday, January 6, 2009

Obesity's Cellular Traffic Jam

Super-sized: Reducing protein traffic jams inside the cells of obese mice helps them lose weight when they are also treated with leptin, an appetite-suppressing hormone.
Credit: Umut Ozcan

The fat hormone leptin was once thought of as a potential obesity wonder drug, but the reality has proved more complex. Leptin is a signal released by fat cells that tells the brain when to stop eating, and initially it showed promise in treating obesity in mice. But now it is known that obese humans actually have high levels of leptin--their brains just become deaf to its signal. This condition, called leptin resistance, has proved trickier to understand and overcome.

A new study published in Cell Metabolism by Harvard Medical School researchers finds that leptin resistance may be a result of a traffic jam in the protein-making part of brain cells: a structure called endoplasmic reticulum (ER), where proteins are created, folded, and sent to other parts of the cell.

Lead author Umut Ozcan, a researcher at Children's Hospital Boston, explains that cells become deaf to leptin when protein production goes awry--a condition called ER stress. "If there's more demand than the ER can handle, proteins start to aggregate," he says. Certain chemical signals can also slow down production, creating the same effect. ER stress leads the cell to release a series of chemical signals in an attempt to fix the situation--a process called the unfolded protein response--and if the condition becomes extreme, the cell may eventually die.

Ozcan had previously linked ER stress in certain body tissues to type 2 diabetes and insulin resistance, which led them to investigate whether the same condition could be tied to obesity. The team discovered that mice fed a high-fat diet showed signs of ER stress in the hypothalamus, the main region of the brain that receives signals from leptin. The researchers then deleted a protein in the hypothalamus of normal mice, which impaired ER function and made cells vulnerable to ER stress. "These mice became severely leptin resistant and started to become obese" when fed a high-fat diet, Ozcan says.

Furthermore, the researchers found that relieving ER stress in obese mice could help restore leptin signaling and alleviate obesity. They used two FDA-approved drugs that have been shown to counteract ER stress and are currently used to treat cystic fibrosis and neurodegenerative disease. These drugs, called PBA and TUDCA, are "chemical chaperones": molecules that increase the ER's capacity to fold proteins. Mice living on a high-fat diet were first treated with one of the chemical chaperones for 10 days, and then treated daily with leptin. This regimen led the mice to eat less and lose between 16 and 19 percent of their body weight, primarily as fat.

"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."