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Leptin-signaling protein maintains normal body weight and energy balance in mice


SH2-B enhances brain’s leptin sensitivity

What do laboratory mice at the University of Michigan Medical School have in common with millions of overweight Americans? Like many of us, these mice just can’t stop eating. They weigh twice as much as their littermates, consume nearly two times as much food, have elevated fatty acid and triglyceride levels, are resistant to insulin, and often develop type 2 diabetes.

Scientists at the University of Michigan Medical School are studying these mice to find out what causes their over-eating and morbid obesity. Is it a character flaw? Do the mice lack self-discipline? Is it from living in a fast-food society? How about the absence of a signaling molecule called SH2-B?

Liangyou Rui, Ph.D., an assistant professor of molecular and integrative physiology in the U-M Medical School, says the answer is SH2-B – a protein he discovered eight years ago while he was a U-M graduate student.

"SH2-B is an intracellular signaling molecule that increases the body’s sensitivity to leptin, a hormone which regulates energy balance and body weight in humans and animals," Rui says. "SH2-B interacts with JAK2 – a key signaling protein that mediates how cells respond to a variety of hormones, including leptin."

One of several hormones produced by fat tissue, leptin’s job is to keep the brain informed about the amount and availability of nutrients stored in body fat.

"We believe leptin sensitivity is determined by a balance between positive and negative regulators," Rui explains. "Previously we only knew the negative regulators. Now we’ve demonstrated that SH2-B is the first example of an intracellular signaling protein with a positive, rather than negative, effect on leptin signal transduction. Our research with mice that lack the SH2-B gene, and so can’t make SH2-B protein, indicates its presence is required to maintain normal energy metabolism and body weight in mice."

The latest U-M research results on SH2-B and how it regulates the brain’s sensitivity to leptin will be published in the August 2005 issue of Cell Metabolism.

"The more fat you have in your body, the higher the concentration of leptin in the bloodstream," Rui says. "Leptin sends a powerful signal to the brain saying: We have a surplus. Reduce feeding and increase energy expenditures."

Leptin’s signal is received by the hypothalamus – the part of the brain that regulates the endocrine system and the autonomic nervous system. In response, neurons in the hypothalamus send out chemical signals called neuropeptides, which suppress appetite and make us stop eating. When the system works properly, the body maintains a natural balance between energy taken in as food and energy expended in activity.

"It’s like the feedback mechanism on a thermostat set to maintain room temperature at 72 degrees," Rui explains. "Our brain has a similar set point for body weight, which is different for every person, because it is determined by genetics subject to modification by environmental factors. Sensitivity to leptin in the hypothalamus may be a key determinant of this set point."

When leptin travels through the bloodstream and reaches the hypothalamus, two types of neurons respond to its signal. Orexigenic neurons produce neuropeptides that promote eating. Neuropeptides produced by anorexigenic neurons, on the other hand, inhibit eating. To send its "stop eating" signal, leptin increases production of anorexigenic neuropeptides, while it inhibits production of orexigenic neuropeptides.

When Rui’s research team measured neuropeptides produced by hypothalamic neurons in mice without SH2-B and compared results to those from normal mice, they found major differences.

"Even though blood levels of leptin in SH2-B null mice were dramatically higher than in normal littermate controls, orexigenic neuropeptide levels were twice as high as in normal mice," says Decheng Ren, Ph.D., U-M research fellow and first author of the Cell Metabolism study. "Deleting SH2-B impairs the sensitivity of these hypothalamic neurons to leptin, and may contribute to over-eating and obesity in SH2-B null mice."

To see whether metabolic differences in energy expenditure, rather than over-eating, were responsible for the obesity of the SH2-B null mice, Ren measured oxygen intake, carbon dioxide production and body heat produced during a 24-hour cycle.

"Surprisingly, mice deficient in SH2-B consumed much more oxygen and generated more carbon dioxide and body heat than normal mice," Ren says. "Overall, their energy expenditure was 63 percent higher than littermate controls. But even though their energy expenditures were higher, mice without SH2-B still become obese, primarily because of their extreme over-eating."

Injecting SH2-B deficient mice with supplemental mouse leptin didn’t affect their food intake or weight gain, although it significantly reduced both weight and eating behavior in normal control mice.

"These results demonstrate that deletion of the SH2-B gene causes severe leptin resistance, which appears to be the major factor responsible for obesity in our experimental mice," Rui says.

In future research, Rui hopes to learn exactly how SH2-B modulates leptin sensitivity in deferent hypothalamic neurons, and hopes to learn more about the set point for energy homeostasis and body weight in the brain. He also will continue his previous research on how SH2-B contributes to the development of insulin resistance and type 2 diabetes. And he wants to join forces with a clinical collaborator to screen patients with obesity and diabetes for potential mutations in the human SH2-B gene.

Sally Pobojewski | EurekAlert!
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