Scripps Florida Scientists Awarded $2.35 Million to Study New Obesity Treatment

By Eric Sauter

The Scripps Research Institute has been awarded a $2.35 million grant from the National Institutes of Health to study a new way of treating obesity as part of a national consortium with the Dana-Farber Cancer Institute.

The long-term aim of the research is to develop compounds that can control the formation and function of a particular type of fat cell that burns calories and reduces weight.

Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, and Theodore Kamenecka, associate scientific director of the Translational Research Institute, are consortium principal investigators, along with Bruce M. Spiegelman, of the Boston-based Dana-Farber Cancer Institute and Harvard Medical School.

The total for the three-year award, a highly competitive National Institutes of Health Director's Opportunity Grant, is $4.2 million with $2.35 million going to Scripps Research in Florida.

"This grant speaks to the critical research components we have developed at Scripps Florida," Griffin said, "plus the fact that we have a host of resources that aren't found anywhere else in academia. Bruce Speigelman is expert in the understanding of fat and energy utilization, and we're experts in understanding how certain receptors are activated and modulated by small molecule drugs, which is central to the success of the research. Our collaboration offers the best team possible to exploit this potentially life-changing biology."

The new research is aimed at creating new therapeutic approaches to the national problem of obesity based on regulating brown fat, a type of cell that plays a critical role in controlling metabolic rates and fighting obesity. Western countries - the U.S. in particular - are in the midst of a growing epidemic of obesity and its associated problems, including high blood pressure, type 2 diabetes, and certain cancers. Currently, there are no generally effective medical therapies to treat obesity, and efforts so far have been limited to education extolling diet and exercise and in extreme cases surgery.

"This type of grant, the Director's Opportunity grant, is aimed at large and critically important projects that have the potential to impact clinical care and public health," Griffin said. "Our joint project will take the discoveries and insight in Bruce's laboratory, develop assays for these novel targets, and look to develop compounds that stimulate white fat to burn calories in the intense way that brown fat does."

Brown fat, which has been identified in healthy humans, serves as a kind of molecular mammalian furnace, generating heat by burning large numbers of calories in creatures like newborn babies (and rodents) that lack the ability to shiver effectively to keep warm. The fat gets its name because it is loaded with mitochondria, the cell's energy plant, which contains iron and gives the fat its red-brown tint. Mitochondria use nutrients to produce energy for the cell.

The grant, Griffin said, is built on several key discoveries the team has made over the last few years. One is the initial discovery of PRDM16, a protein capable of determining whether certain types of immature cells will develop into brown fat cells. The protein works in tandem with another protein and together they act as the catalyst to the development of brown fat in different cell types. One aim of the funded research program will be to investigate regulation of whole body energy homeostasis and to isolate and characterize a type of brown fat cell in white fat tissues with substantial heat-producing capacity. This will be combined with the synthesis and evaluation of small molecules that can regulate PRDM16's activity.

A second discovery by the research team, which was published earlier this year in the journal Nature, was a novel signaling pathway trigged by phosphorylation of PPARg, the molecular target of the antidiabetic drugs called thiazolidenediones or TZDs. The research team is building on this discovery and is in the process of generating proof-of-concept compounds that modulate only this pathway. These compounds, in addition to being antidiabetic, have the potential to enhance brown fat leading to weight loss.

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"This grant speaks to the critical research components we have developed at Scripps Florida, plus the fact that we have a host of resources that aren't found anywhere else in academia," says Patrick Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. (Photo by Lucien Capehart.)