Mice lacking a functional copy of the SH2-B gene were smaller at birth than normal mice. After 5 weeks of age, however, the mice began gaining weight rapidly and were about twice as heavy as normal littermates after several months, with at least a 2.8-fold increase in body fat content.
The mice also exhibited a near doubling of blood lipid levels and their livers grew to more than twice their normal size owing to a massive accumulation of fat, Rui said.
Moreover, the animals developed severely elevated blood sugar, insulin, and leptin concentrations. Elevated leptin levels are a hallmark of leptin resistance, a primary risk factor for obesity, he added.
Further examination found that the animals lacking SH2-B ate nearly twice as much as normal. Surprisingly, Rui said, the animals burned more calories; however, the animals still have a net positive energy imbalance of more than 60% higher than normal animals at 18?9 weeks of age, owing to voracious feeding. The mice also exhibited defects in the leptin signaling pathway in brain cells of the hypothalamus, they report.
Earlier studies have found that mice lacking leptin show marked obesity that is restored following leptin treatment, Rui said. However, obese animals, with high blood concentrations of the hormone, often exhibit resistance to leptin's usual effects. As a result, leptin itself has proven to be insufficient for obesity therapy.
The new findings reveal SH2-B as a critical component in maintaining leptin sensitivity, Rui said. Therefore, SH2-B and signaling events regulated by SH2-B may serve as potential therapeutic targets for the treatment of obesity and type 2 diabetes.
"Because SH2-B sensitizes both leptin and insulin, action drugs that mimic or enhance SH2-B action may improve insulin and leptin sensitivity and have potential