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Weight control protein may yield antiobesity drugs

Cell Press

A weight control protein with a key role in the brain's ability to monitor body fat content may yield new approaches for treating obesity and type 2 diabetes, according to a new report in the August issue of Cell Metabolism. The findings in mice further suggest that particular variants of the protein SH2-B might underlie obesity in humans, the researchers said.

SH2-B, which has multiple functions in cells throughout the body, keeps the brain sensitive to the fat hormone leptin, found researchers from the University of Michigan Medical School. Produced by fat tissue, the leptin hormone sends signals to the brain about the body's fat content. That signal, in turn, elicits adjustments in appetite and energy expenditure to maintain normal body weight.

Mice lacking SH2-B overeat and become obese, the team found. The animals additionally develop a metabolic syndrome characterized by high blood concentrations of leptin, insulin, and lipids. They also develop fatty livers and high blood sugar, the group reports.

"Our findings reveal SH2-B as an important positive regulator of leptin sensitivity inside cells of the brain region known as the hypothalamus," said senior author of the study, Liangyou Rui. The hypothalamus is a key area in the central nervous system that integrates neuronal, hormonal, and nutrient-related signals to maintain body weight, he explained.

Leptin is a hormone produced by fat that normally decreases food intake and increases energy expenditure. In many species, including humans, the hormone acts to stabilize weight and glucose balance through activating its receptors in the hypothalamus.

Earlier work by Rui's group found that SH2-B binds to a second protein, JAK2, to promote leptin signaling in cultured cells. Further work then identified a physiological role for SH2-B in the regulation of blood glucose; mice deficient for the protein develop insulin resistance and type 2 diabetes, they found.

The current study shows that SH2-B also regulates energy balance and body weight by enhancing leptin sensitivity in animals, Rui said.

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 18-19 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 value in treatment of obesity and type 2 diabetes," he added.

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The researchers include Decheng Ren, Minghua Li, Chaojun Duan, and Liangyou Rui of the University of Michigan Medical School in Ann Arbor, Michigan. This study was supported by Career Development Award from the American Diabetes Association and NIH (both to L.R.). This work utilized the cores supported by the Michigan Diabetes Research and Training Center, University of Michigan's Cancer Center, and University of Michigan Center for Integrative Genomics.

Ren et al.: "Identification of SH2-B as a Key Regulator of Leptin Sensitivity, Energy Balance and Body Weight in Mice" Publishing in Cell Metabolism, Vol. 2, August 2005, pages 95-104. DOI 10.1016/j.cmet.2005.07.004 www.cellmetabolism.org.

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