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The Fats of Life

  • Date: 5/15/2012

JPB FoundationResearchers explore the molecular underpinnings of diabetes and obesity

It is the leading cause of kidney failure, non-trauma-related lower-limb amputations, and new cases of blindness among adults in the United States. It is a major cause of heart disease and stroke and is the seventh leading cause of death in this country. "It" is diabetes-and, while there are many treatment options, very few are fully successful in preventing the complications for the 25.8 million people living with the disease.

Obesity and type 2 diabetes have reached "epidemic" proportions: as rates of obesity increase, they lead to corresponding increases in the prevalence of diabetes. "Understanding how obesity and diabetes interact may lead to the design of better drugs or better therapies," says Eleftheria Maratos-Flier, M.D., professor of medicine at Harvard Medical School (HMS), director of the Office of Academic Careers, and a member of the Division of Endocrinology, Diabetes, and Metabolism at BIDMC, which is on the leading edge of investigations into the pathogenesis of type 2 diabetes.

Maratos-Flier and division colleague Barbara Kahn, M.D., vice chair for research strategy in the Department of Medicine and George R. Minot Professor of Medicine at HMS, are two of five principal investigators on a nationwide collaboration of metabolic research projects funded by The JPB Foundation. They were each awarded a one-year grant of $450,000 to support their work on understanding the link between diabetes and obesity in order to find new preventive strategies, treat-ments, or biomarkers. "The JPB Foundation is dedicated to funding new and important diabetes research, including novel concepts that may not be ready for NIH funding," Kahn says. "The foundation is very broad minded and is interested not only in very basic research but also in getting diabetes and nutrition education to underserved people in the community."

Kahn and her team have a long track record of important discoveries regarding the molecular mechanisms underlying obesity and type 2 diabetes. "Usually people think pro-duction of lipids is a bad thing metabolically," Kahn explains. But her lab recently demonstrated that synthesizing fatty acids in adipose tissue is beneficial in terms of preventing diabetes. "One important difference is whether the lipids are being produced in fat or in the liver. If you produce the fatty acids in the adipose tissue, it keeps them out of muscle and liver and it drives the glucose into the fat so it is not building up in the blood."

Because fatty acids are often thought to be detrimental metabolically, her team investigated what types of lipids were being made in mice they genetically engineered. Kahn established a collaboration with chemists at Harvard University and together they discovered a novel family of lipids elevated in insulin-sensitive mice and also present in humans. Kahn is now investigating the process of producing lipids in fat, the structure and biological functions of the novel lipids, and which of those lipids are favorable in terms of preventing or treating diabetes.

Meanwhile, Maratos-Flier, who also has extensive experience in the field, worked on the specific effects of diet composition on metabolism looking at both high-fat/high-sugar western style diets and very low carbohydrate diets. Using this model, her team discovered that protein FGF21 has several important metabolic roles, including driving oxidation of fatty acids in the liver and thus limiting liver lipid content. In addition, her group explored the role of FGF21 in the conversion of white fat, which stores calories, into brown fat, which generates heat.

The research team compared the responses of normal mice and mice without FGF21 to cold exposure. They found that the deficient mice were not effective in converting white fat into brown fat. Treatment with FGF21 at normal temperatures mimicked cold exposure and led to conversion of white fat to brown fat. "That could make FGF21 an amazing therapeutic for both weight loss and possibly type 2 diabetes," says Maratos-Flier, who is inves-tigating the molecular determinants of that process. She is also investi-gating the incidence of FGF21 in the acinar pancreas and its relation to the islet cells, which produce insulin. "We know FGF21 lowers blood sugar," Maratos-Flier explains, "but whether it is acting on islets to lower blood sugar is not really particularly well known."

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