Leptin-signaling Protein Maintains Normal Body Weight And Energy Balance In Mice

They weigh twice as much as their littermates, consume nearly twotimes 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 arestudying these mice to find out what causes their over-eating andmorbid obesity. Is it a character flaw? Do the mice lackself-discipline? Is it from living in a fast-food society? How aboutthe absence of a signaling molecule called SH2-B?

Liangyou Rui, Ph.D., an assistant professor of molecular andintegrative physiology in the U-M Medical School, says the answer isSH2-B -- a protein he discovered eight years ago while he was a U-Mgraduate student.

"SH2-B is an intracellular signaling molecule that increasesthe body's sensitivity to leptin, a hormone which regulates energybalance and body weight in humans and animals," Rui says. "SH2-Binteracts with JAK2 -- a key signaling protein that mediates how cellsrespond to a variety of hormones, including leptin."

One of several hormones produced by fat tissue, leptin's job isto keep the brain informed about the amount and availability ofnutrients stored in body fat.

"We believe leptin sensitivity is determined by a balancebetween positive and negative regulators," Rui explains. "Previously weonly knew the negative regulators. Now we've demonstrated that SH2-B isthe first example of an intracellular signaling protein with apositive, rather than negative, effect on leptin signal transduction.Our research with mice that lack the SH2-B gene, and so can't makeSH2-B protein, indicates its presence is required to maintain normalenergy metabolism and body weight in mice."

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

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

Leptin's signal is received by the hypothalamus -- the part ofthe brain that regulates the endocrine system and the autonomic nervoussystem. In response, neurons in the hypothalamus send out chemicalsignals called neuropeptides, which suppress appetite and make us stopeating. When the system works properly, the body maintains a naturalbalance between energy taken in as food and energy expended inactivity.

"It's like the feedback mechanism on a thermostat set tomaintain room temperature at 72 degrees," Rui explains. "Our brain hasa similar set point for body weight, which is different for everyperson, because it is determined by genetics subject to modification byenvironmental factors. Sensitivity to leptin in the hypothalamus may bea key determinant of this set point."

When leptin travels through the bloodstream and reaches thehypothalamus, two types of neurons respond to its signal. Orexigenicneurons produce neuropeptides that promote eating. Neuropeptidesproduced by anorexigenic neurons, on the other hand, inhibit eating. Tosend its "stop eating" signal, leptin increases production ofanorexigenic neuropeptides, while it inhibits production of orexigenicneuropeptides.

When Rui's research team measured neuropeptides produced byhypothalamic neurons in mice without SH2-B and compared results tothose from normal mice, they found major differences.

"Even though blood levels of leptin in SH2-B null mice weredramatically higher than in normal littermate controls, orexigenicneuropeptide levels were twice as high as in normal mice," says DechengRen, Ph.D., U-M research fellow and first author of the Cell Metabolismstudy. "Deleting SH2-B impairs the sensitivity of these hypothalamicneurons to leptin, and may contribute to over-eating and obesity inSH2-B null mice."

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

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

Injecting SH2-B deficient mice with supplemental mouse leptindidn't affect their food intake or weight gain, although itsignificantly reduced both weight and eating behavior in normal controlmice.

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

In future research, Rui hopes to learn exactly how SH2-Bmodulates leptin sensitivity in deferent hypothalamic neurons, andhopes to learn more about the set point for energy homeostasis and bodyweight in the brain. He also will continue his previous research on howSH2-B contributes to the development of insulin resistance and type 2diabetes. And he wants to join forces with a clinical collaborator toscreen patients with obesity and diabetes for potential mutations inthe human SH2-B gene.

Rui's research issupported by the American Diabetes Association and the NationalInstitutes of Health (NIDDK). The University of Michigan has appliedfor a patent on SH2-B. In addition to Ren, other U-M collaborators onthe study were research fellows Minghua Li, Ph.D., and Chaojun Duan,M.D.