SOCS-3 and Obesity
The discovery of a protein that apparently prevents people from feeling full after a big meal could lead to effective new drugs against obesity. The protein, called SOCS-3, blocks signals from the brain that normally shut down appetite when the body’s fat cells have had their fill, Harvard University researchers have found.
Their work follows up the 1995 discovery of leptin, a natural hormone that discourages overeating. (The name comes from the Greek work “leptos,” which means “thin.”)
Normally, as people or animals eat, their fat cells produce leptin, which travels to the brain and triggers that sated feeling. Scientists at Rockefeller University showed three years ago that mice lacking a working gene to regulate production of leptin become massively obese. When treated with injections of the hormone, the massive mice dropped 40 percent of their weight in a month.
Was this a cure for obesity, a nutritional “disease” that affects one out of every three adults in the United States as well as a substantial number of their children? While some tabloids and magazines raised hopes in that direction, it was not to be.
“The vast majority of obese people, 99.9 percent of them, make enough leptin,” explains Jeffrey Flier, a professor of medicine at Harvard Medical School and researcher at Harvard-affiliated Beth Israel Deaconess Medical Center in Boston. “But they are resistant to it.”
In normal people, the leptin travels from fat cells to the hypothalamus, a pea-sized region deep in the brain that regulates hunger, thirst, sex, and number of other vital functions. When leptin docks with receptors on the hypothalamus, it initiates what Flier calls “a cascade” of activity that should result in satiety. But for large numbers of people, that just doesn’t happen.
A Balanced Appetite
“We set ourselves the goal of determining the reason for leptin resistance,” Flier says of his research team.
Last year, they read a scientific paper about proteins called SOCS (Suppressors Of Cytokine Signaling) proteins. Leptin belongs to the cytokine family, so they decided to see how SOCS affects leptin.
That idea turned out to be a good one. After Flier and his colleagues injected leptin into resistant strains of mice, they discovered indications of an oversupply of SOCS-3 in the brains of mice.
“When leptin is injected, some cells in the brain respond to it and others act to inhibit its activity,” Flier explains. “The two processes work by a different pathway, and we think this provides a balance that prevents things from going too far in either direction.”
At least some, if not many cases of obesity may be caused by such an imbalance. Obesity is defined as being 20 percent above the ideal weight. A person with severe obesity might have a feedback system more out of balance than someone who is mildly or moderately obese.
This idea remains to be proven. Both SOCS-3 and leptin are present in humans, but it’s not known whether they work together as they do in mice. Flier’s group is collaborating with other researchers who have collected tissue from the hypothalamuses of deceased obese and lean people.
“If SOCS-3 occurs in higher amounts in obese people than in thin people, that would be good evidence we’re on the right track,” Flier says.
The next step would be to develop a drug to block SOCS-3 and free leptin to do its work of limiting appetites. Flier’s group is already working with Eli Lilly & Co. on such a treatment.
However, some basic biology is required before such a pill becomes a reality. The details of how leptin works on the brain to make people lose their appetites remains unknown. Exactly what part of the cascade does SOCS-3 inhibit and how? Any drug developed must hit a very specific target. The hypothalamus is sometimes called “the brain of the brain” because it regulates so many functions; an appetite drug must not disturb these other functions. That is, it can’t have dangerous side effects.
The stakes are high. Obesity takes a huge toll on the nation’s health, raising risks of heart disease, strokes, and diabetes. The more someone is overweight, the higher the risk. Health costs directly attributable to the disease reach to an estimated $68 billion a year. An additional $30 billion is spent each year on weight-reduction programs and special foods.
