"With obesity at epidemic levels, finding new ways to treat it is one of medicine's holy grails," said C. Ronald Kahn, M.D., President of Joslin Diabetes Center, the Mary K. Iacocca Professor of Medicine at Harvard Medical School (HMS), and principal investigator of the study that appears in the June edition of the journal Nature Cell Biology. In laboratory studies of mouse cells, his research team identified genes that govern how precursor cells give rise to mature brown fat cells.

There are two main types of fat cells in the body -- white and brown. White fat cells are the "conventional" form of fat that we all recognize. They are designed to store energy for use in times of need. Chocked full of lipid droplets, these big cells accumulate under the skin and around internal organs.

By contrast, the main role of brown fat cells is to burn energy and generate heat. They contain small lipid droplets tucked between tiny energy factories called mitochondria. In mice, brown fat cells are found throughout the body and are present during the entire life cycle. In humans, they are principally found in the neck area of newborns, helping their tiny bodies generate heat. Brown fat cells largely disappear by adulthood, but their precursors still remain in the body, lodged in white-fat depots.

Because brown fat cells burn calories, Joslin scientists theorized that finding ways to encourage the development of brown fat might be good for treating obesity. In previous research, the scientists were among the first to develop cell lines of precursor cells that give rise to brown fat cells. "We used those cell lines to study how insulin affects the conversion of fat precursors, or preadipocytes, into mature brown adipocytes," said Yu-Hua Tseng, Ph.D., who with Atul J. Butte, M.D., Ph.D., of Boston's Children's Hospital and HMS, served as first author of the study. Others from Joslin's Cellular and Molecular Physiology research section who participated in the study included former Joslin fellows Efi Kokkotou, M.D., Ph.D., now at Beth Israel Deaconess Medical Center, and Vijay K. Yechoor, M.D., now at Baylor College of Medicine; Cullen M. Taniguchi, M.D., Ph.D., HMS student; Kristina M. Kriauciunas of Joslin; Joslin fellow Aaron M. Cypess, M.D., Ph.D.; Michio Niinobe, Ph.D., and Kazuaki Yoshikawa, M.D., Ph.D. of Osaka University, Japan; and Joslin Investigator Mary-Elizabeth Patti, M.D.

The researchers compared cell lines from normal "wild-type" mice to cells lines from mice that genetically lacked key components of the insulin-signaling network which are important to insulin's role in letting food nutrients enter the body's cells. If cells resist insulin, the body cannot get the energy it needs. This "insulin resistance" is the main culprit in the onset of in type 2 diabetes. Being overweight or obese has long been implicated with insulin resistance and type 2 diabetes and also raises the risk for heart disease, stroke and cancer.

The Joslin team studied "knockout" cell lines of brown preadipocytes that lacked insulin receptor substrates (IRS) numbered 1 through 4, which are the first steps in insulin signaling inside the cell. In cell lines lacking IRS1, the precursors failed to develop into mature brown fat cells. Importantly, when they added the gene for IRS1 back into the knockout cells, the precursors recovered most of their ability to differentiate into brown fat cells. Varying effects occurred with the knockout of genes for IRS2, IRS3 and IRS4. Using DNA chips to analyze these cells, a strong genetic pattern emerged that predicted the potential of precursors to differentiate into mature brown fat cells.

Of the 347 genes that were altered in the cells that could not form brown fat, one of the most over-expressed was for a protein called necdin. Until this study, necdin was associated largely with nerve tissue and Prader-Willi syndrome, a neurodevelopmental disorder in children characterized by mental retardation, feeding problems and obesity. The Joslin researchers discovered that reducing the level of necdin is essential for precursor cells to give rise to brown fat cells. They also found that a transcription factor called CREB is involved in this reduction.

"For now, diet, exercise and medication is the best approach for helping the body overcome insulin resistance and controlling type 2 diabetes," said Dr. Kahn. "But for people who are genetically predisposed to obesity, that approach often doesn't work. As we learn more about the genesis of brown fat cells and the genes governing them, we may be able to target those genes with drugs or other agents to create powerful tools to fight obesity."

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