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Shifting the Balance Between Good Fat and Bad Fat

Protein p62 regulates metabolism in fat tissue, may offer therapeutic target for obesity (Jan. 4)

In many cases, obesity is caused by more than just overeating and a lack of exercise. Something in the body goes awry, causing it to store more fat and burn less energy. But what is it? Researchers at the Sanford–Burnham Medical Research Institute in Orlando, Fla., have a new suspect — a protein called p62. According to the researchers’ findings, published in the Journal of Clinical Investigation, when p62 is missing in fat tissue, the body’s metabolic balance shifts — inhibiting “good” brown fat (which burns calories), while favoring “bad” white fat. The discovery suggests that p62 might make a promising target for new therapies aimed at curbing obesity.

Some researchers believe that muscle tissue — where energy is expended — controls obesity. Others suspect that the liver is a key player, or that the brain’s appetite control center is most responsible for obesity. Many now believe that brown fat somehow malfunctions in obesity, but the details are unclear.

In the new study, researchers set out to identify the specific tissue responsible for obesity when p62 is missing. They made several different mouse models — each missing p62 in just one specific organ system, such as the central nervous system, the liver, or muscle. In every case, the mice were normal weight. They weren’t obese, like mice that lacked p62 everywhere.

Then the investigators made a mouse model lacking p62 only in fat tissue. These mice were obese, just like the mice missing p62 in all tissues. Upon further study, the researchers found that p62 blocks the action of an enzyme called extracellular signal-regulated kinase (ERK) while activating another enzyme, known as p38. When p62 is missing, p38 is less active in brown fat, while ERK is more active in white fat. As a result, p62 acts as “a master regulator” in normal fat metabolism.

According to Jorge Moscat, PhD, the discovery of p62’s role in brown fat tissue is encouraging because fat tissue is much more accessible than other parts of the body — the brain, for example — for potential drug therapies. “This makes it easier to think about new strategies to control obesity,” he said.

Source: Sanford–Burnham Medical Research Institute; January 4, 2013.

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