A protein called SH2B1 regulates whether mice gain weight or stay skinnier and healthier.

Previously, Rui and his team have shown that mice that lack the gene for SH2B1 -- called knockout mice -- become obese, diabetic, and unable to stop eating. Their bodies lose the ability to sense the signals sent by leptin and insulin that tell the brain to slow down food intake and fat storage.

For the new paper, they looked at not only normal mice and mice that didn’t have the SH2B1 gene, but also at mice that made SH2B1 only in brain cells, either in normal or larger-than-normal amounts. They found that restoring SH2B1 just in the brain completely corrected the metabolic disorders that the knockout mice had developed, but also improved the brain cells’ ability to respond to leptin signals and produce further signals that regulate eating.

What’s more, the mice that were treated to make extra SH2B1 didn’t become obese or lose their ability to respond to leptin signals even after being fed a high-fat diet that caused those effects in other mice.

More SH2B1 means less obesity. So any drug or gene therapy that would increase SH2B1 will probably decrease hunger and cause weight loss.

“Obesity, whether in mice or humans, is the product of an altered balance between energy intake and energy use. The imbalance is linked to alterations in leptin and insulin signaling that lead to excess weight gain and Type 2 diabetes, respectively,” says Rui, an assistant professor of molecular and integrative physiology at U-M. “SH2B1 appears to play a key regulatory role in this system, through its direct influence on the processing of leptin and insulin signals in cells of the brain’s hypothalamus.”

Do people who are naturally skinny have genetic variations that causes their brain cells to make more SH2B1?

SH2B1 binds to an enzyme called a kinase that places phosphate groups onto other proteins. The kinases typically activate and deactivate other proteins. So SH2B1 changes whether tyrosine kinase regulates other proteins.

The team and other researchers have found that SH2B1, which was previously called SH2-B, is a kind of jack-of-all-trades in the world of cell signaling. Able to shuttle between the area just beneath the cell membrane and the nucleus, it can bind to many different molecules and facilitate signaling.

Specifically, it can bind to a variety of molecules called tyrosine kinases, including ones that serve as receptors for insulin and growth factors that circulate in the brain and body. One of its most important binding partners is JAK2, which is activated every time a leptin molecule binds to a cell.

Since leptin is the body’s messenger boy to the brain for “stop eating, we’re full” messages, and JAK2 helps receive those messages as they arrive, SH2B1’s partnership with JAK2 is an important one. In a previous paper, Rui and his former mentor and current colleague Christin Carter-Su, Ph.D., showed that SH2B1 encourages the action and production of JAK2, unlike two other proteins that have been shown by other teams to reduce its activity. Carter-Su is a professor of molecular and integrative physiology and heads the biomedical research division of the Michigan Diabetes Research and Training Center.

These scientists and many others are gradually piecing together a very detailed model of how the feeling of hunger is regulated in the brain. With better understanding of a complex systems comes better ability to manipulate it. The identification and study of every piece eventually leads to candidate targets for drug development and ideas for how to alter the environment of cells to cause them to act differently.