Scientists say thay have successfully reversed obesity in mice by manipulating the production of an enzyme known as tyrosine-protein kinase-2 (Tyk2). In their experiments, the team at the Virginia Commonwealth University Massey Cancer Center discovered that mice lacking Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT), and they claim that this applies to humans as well.
The researchers say the study is the first to provide evidence of the relationship between Tyk2 and brown fat. Previous studies by the team, led by Andrew Larner, M.D., Ph.D., revealed that Tyk2 helps suppress the growth and metastasis of breast cancer, and now the current study suggests this same enzyme could help protect against and even reverse obesity.
Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high-fat diet and in obese humans. The scientists were able to reverse obesity in mice that do not express Tyk2 by expressing a protein known as signal transducer and activator of transcription-3 (Stat3). Stat3 mediates the expression of a variety of genes that regulate a host of cellular processes. Tyk2-negative mice expressing CAStat3 transgene in brown fat also show improved BAT development, normal levels of insulin, and significantly lower body weights. The researchers found that Stat3 formed a complex with a protein known as PR domain containing 16 (PRDM16) to restore the development of BAT and decrease obesity.
“We discovered that Tyk2 levels in mice are regulated by diet. We then tested tissue samples from humans and found that levels of Tyk2 were more than 50 percent lower in obese humans,” says Dr. Larner, Martha Anne Hatcher distinguished professor in oncology and co-leader of the cancer cell signaling program at VCU Massey Cancer Center. “Our findings open new potential avenues for research and development of new pharmacological and nutritional treatments for obesity.”
There are two different types of fat—white adipose tissue and BAT. White fat is the primary site of energy storage. BAT is responsible for energy expenditure in order to maintain body temperature. BAT deposits are present in all mammals, but until recently, scientists thought BAT was only active in infants and not in adult humans. Only in the last four years have scientists realized that BAT is present in adults and helps to regulate energy expenditure. Additionally, research has shown that diminished BAT activity is associated with metabolic syndrome, a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.
“We have made some very interesting observations in this study, but there are many questions left unanswered,” Dr. Larner cautions. “We plan to further investigate the actions of Tyk2 and Stat3 in order to better understand the mechanisms involved in the development of brown adipose tissue. We’re hopeful this research will help lead to new targets to treat a variety of obesity-related diseases such as cancer, cardiovascular disease, and diabetes.”
The study was published in the online edition of the journal Cell Metabolism in an article titled “Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity”.