Diabetes Center Researcher Identifies Gene Responsible for Control of Brown Fat Development

Discovery of EHMT1’s role has tremendous implications for battle against obesity and related metabolic disorders, including insulin resistance. Shingo Kajimura, PhD, a researcher in the Diabetes Center and a member of the Department of Cell and Tissue Biology at UC San Francisco, has identified a gene vital to the development and function of brown fat cells.

The discovery may ultimately lead to effective therapies for battling obesity and metabolic diseases. Dr. Kajimura’s findings appeared in the November 6 issue of the journal Nature.

All mammals, including humans, have two types of fat tissue: white fat, used to mainly store excess energy and found in the “problem zones” of overweight people and brown fat, used to burn calories and generate heat to maintain body temperature.

Over the last several years, interest in brown fat has exploded, as researchers have recognized the therapeutic potential of brown fat to counteract obesity and obesity-related diseases, including insulin resistance in adult humans.

One of the major goals of the Kajimura lab is to activate brown fat development through pharmacological approaches. To achieve this objective, the team has been searching for potential drug targets, including the molecular factors that stimulate brown fat development.

In prior studies, Dr. Kajimura and his colleagues demonstrated that white fat could be converted into brown fat in culture and in mouse models. The key to this conversion was a protein called PRDM16, which is found in both humans and mice.

“Our previous work showed that the PRDM16 pathway delivers the fuel for brown fat development, but we also wanted to identify the engine behind PRDM16’s actions,” said Dr. Kajimura. “By gaining a better understanding of the mechanisms that control PRDM16, we felt we could also shed additional light on how brown fat develops in the body naturally, and once created, how it manages to burn calories to generate heat.”

To address these questions, Dr. Kajimura studied the link between PRDM16 and a gene called EHMT1, mutations in which have been implicated in human obesity. In mouse models, he and his team proved that: 1) EHMT1 is a necessary ingredient in the differentiation of stem cells into brown fat cells, and 2) that the gene controls the energy-burning function of brown fat cells by stabilizing the PRDM16 protein. Further underscoring the importance of EHMT1, Dr. Kajimura and his colleagues also confirmed that mutations in EHMT1 can negatively impact the development and function of brown fat cells, leading to obesity and insulin resistance.

These crucial findings make EHMT1 a possible target for future obesity drugs.