Deleting neural STAT3 protein in mice

Protein molecules that help maintain a healthy body temperature, electrolyte balance, respiration, heart rate, and other critical functions, also appear to regulate weight and fertility, according to Yale researchers.

STAT3 proteins are regulatory molecules that signal cell functions for activating genes. When the STAT3 molecules are disrupted in mice, the animals either die before they are born, or overeat and become obese, diabetic and infertile, according to the study published in the Proceedings of the National Academy of Sciences.

Mice with disrupted STAT3 begin to gain weight at six to eight weeks old and weigh twice as much as normal mice by adulthood. The excess body mass was almost exclusively fat. Livers of the mice also were severely enlarged with fat deposits.

The senior author, Xin-Yuan Fu, of the Department of Pathology at Yale School of Medicine, said the study contradicts previous research that concluded STAT3 plays no role in reproduction and growth and only a marginal role in glucose regulation.

The study also raises more questions about leptin, a protein produced by fat cells and thought to play an important role in signaling the reduction of body fat.

“The mutant mice had an oversupply of leptin, yet still became obese, suggesting a leptin-resistant condition,” Fu said.

During embryonic development, STAT3 is found in areas of the brain where nerve cell proliferation and differentiation take place. In adults, STAT3 has been implicated in the regulation of energy balance through its effect on leptin. This new study provides direct evidence for this role.

Fu said the study shows that body weight and fertility are essentially controlled through STAT3 functions in the brain. These discoveries, he said, could help in the development of new therapeutics to treat obesity and infertility.

Citation: Proceedings of the National Academy of Sciences, Vol. 101: 4661-4666 (March 30, 2004)