Studying Fat on a Fast Track
Adult mice that rapidly regrow fat cells and insulin-producing cells will aid research on obesity and diabetes.
BOSTON – (January 17, 2017) – Scientists at Joslin Diabetes Center have developed adult mice that can generate white fat and brown fat surprisingly quickly, providing a powerful new research model for obesity, diabetes and other metabolic conditions.
C. Ronald Kahn, M.D., is Chief Academic Officer at Joslin Diabetes Center. Dr. Kahn is co-head of the section on Integrative Physiology & Metabolism and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.
“We’re excited about using this model to look at growth factors of two sorts. On one hand, we have a chance to find factors that stimulate or inhibit fat growth to modify the amount of white and brown fat in the body and achieve a better balance for metabolism,,” says C. Ronald Kahn, M.D., senior author on a report on the study published in Cell Metabolism and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.
“On the other hand, in addition to their rapid growth of fat cells, these mice quickly doubled their mass of insulin-producing pancreatic beta cells, and this may provide insight into new factors that could be important in the treatment of type 1 or type 2 diabetes.”
“Indeed, this is the most robust model ever identified for the rapid growth of beta cells,” says Kahn, who is Joslin’s chief academic officer. Researchers have long sought ways to treat diabetes by boosting populations of these cells.
The Joslin scientists began their work by genetically modifying mice so that their fat cells would not respond to signaling by the hormone insulin or by a related hormone that affects cell growth. These gene “knockouts” in the fat cells, however, were only activated when the investigators gave the adult mice a certain drug.
When these mature fat cells lost insulin signaling, the cells began to break down, and the mice soon lost most of their fat. The animals also started to suffer consequences from this severe loss of fat, including insulin resistance, high blood glucose levels and related conditions. In addition, insulin producing beta cells started to grow to compensate for the insulin resistance.
However, once the scientists stopped giving the drug that induces the knockout, the white and brown fat cells came back in a few weeks, while the beta cell growth stimulation stopped.
Clearly, the knockout was driving biological mechanisms that control the growth of fat and beta cells, Kahn says, which raises two possible explanations.
“One possibility is that fat normally makes a substance that slows its own growth, so that when you get rid of fat, this substance is no longer there to inhibit growth,” he says. “If we can identify such a factor, it would be a new therapeutic target for controlling obesity.”
“The other possibility is that the knockout caused the production or release of a substance that stimulates fat growth,” Kahn notes.
“And maybe there are two different kinds of growth factors for white fat and brown fat, since the brown fat came back slower than the white fat. If so, we hope to identify factors that could slow the growth of the white fat and stimulate the growth of the brown fat. By improving this balance between white fat and brown fat, we might improve both obesity and metabolism.”
He and his colleagues also will follow up on the dramatic expansion of beta cell mass seen in these mice, which may help scientists get new clues about ways to accelerate the growth of these cells.
“Overall, we hope our research with this new model may eventually help in treating obesity, diabetes and other metabolic conditions,” Kahn sums up.
Lead author on the Cell Metabolism paper was Masaji Sakaguchi. Co-authors, also from Joslin, included Shiho Fujisaka, Weikang Cai, Jonathon Winnay, Masahiro Konishi, Brian O’Neil, Mengyao Li, Rubén García-Martín, Hirokazu Takahashi, Jiang Hu and Rohit Kulkarni. Lead support was by the National Institutes of Health.
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