Transplantation of genetically modified fat protects mice from obesity and insulin resistance, Glads

By Bill Gordon

Fat has long been recognized as an important source of energy. Surprisingly, however, recent studies have revealed that fat also plays an important role in regulating energy, in part by secreting hormones that govern the storage and use of fat and glucose (or sugar).

Now, investigators at the Gladstone Institute of Cardiovascular Disease have shown that genetically altered fat that is transplanted into normal mice protects the animals from obesity. It also protects them from insulin resistance, which is tightly correlated with obesity and is a hallmark of diabetes.

The model offers a useful strategy for further study of the role of fat in regulating energy, the researchers say, and eventually could lead to insights that would benefit patients. The work is published in the June 1 issue of the Journal of Clinical Investigation.

In their study, the team deleted, or “knocked out,” in mice a gene known as Dgat1, which encodes an enzyme involved in making lipids, or fats. They then took white adipose (fatty) tissue from these mice and transplanted it into normal mice. When these mice were fed a high-fat diet, they remained leaner than mice that did not receive the fat lacking Dgat1. Moreover, the mice that received the genetically modified fat had a twofold increase in the production of adiponectin, a hormone that helps burn fat and improves insulin sensitivity.

The findings suggests, the researchers say, that knocking out the Dgat1 gene perturbs the metabolic function of the fat tissue, leading it to secrete hormones that then send a signal to the rest of the animal to burn more energy.

“The genetically engineered fat seems to function like a mini-pump of the hormone adiponectin, and by inserting this mini-pump into obesity-prone mice, it protects them against obesity. In this sense, it resembles insulin pumps used to treat diabetes,” says Gladstone scientist Hubert Chen, MD, lead author of the study and member of the laboratory of senior author Robert V. Farese, Jr., MD.

The next step in the research, says Chen, is to determine if the beneficial effect of the transplantation is all due to the release of adiponectin, or whether another, yet-to-be-identified molecule is involved. “It’s exciting to be investigating whether some novel molecule could be beneficial for treating obesity and diabetes,” he says.

“The idea that one can transplant genetically modified fat and confer leanness and sensitivity to insulin may have therapeutic potential over the long run,” says Farese.

At the same time, the researchers say, it’s unlikely they will be transplanting genetically engineered fat to treat human obesity or diabetes in the near future. Rather, says Chen, “the technique provides a useful tool for studying the metabolic effects of fat-secreted molecules. New insights regarding these molecules may lead to a better understanding of the causes of obesity and diabetes and provide new treatment strategies.”

The finding builds on the Farese team’s previous research. Several years ago, the researchers discovered the Dgat1 gene, and determined that when they knocked it out in mice the animals expended more energy(i.e., burned more fat), were resistant to obesity, and had increased sensitivity to insulin.

“It wasn’t obvious why deleting a gene involved in making lipids would lead to increased energy expenditure and confer resistance to obesity,” says Chen. The current study was designed to offer insight into the phenomenon.

DGAT1, or acyl CoA:diacylglycerol acyltransferase 1, is one of two enzymes known to catalyze the last step in synthesis of triglyceride, a major energy storage molecule, in mammals.

In addition to their Gladstone appointments, Chen is a clinical instructor of medicine at the University of California, San Francisco (UCSF) and Farese is a UCSF professor of medicine. Their co-authors on the study were Heather M. Myers, B.S. a Gladstone research associate, and Dalan R. Jensen PhD, and Robert H. Eckel, MD, of the University of Colorado Health Sciences Center in Denver.

The study was funded by the National Institutes of Health and the Sandler Family Supporting Foundation and the J. David Gladstone Institutes.

The Gladstone Institute of Cardiovascular Disease is one of three research institutes of The J. David Gladstone Institutes, a private nonprofit biomedical research institution affiliated with UCSF. The institute is named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.