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.