Shifting the balance between good fat and bad fat

LA JOLLA, Calif., January 4, 2013 – In many cases, obesity is caused by more than just overeating and a lack of exercise. Something in the body goes haywire, causing it to store more fat and burn less energy. But what is it? Researchers at Sanford-Burnham Medical Research Institute have a new theory—a protein called p62. According to a study the team published in the Journal of Clinical Investigation, when p62 is missing in fat tissue, the body's metabolic balance shifts—inhibiting "good" brown fat, while favoring "bad" white fat. These findings indicate that p62 might make a promising target for new therapies aimed at curbing obesity.

"Without p62 you're making lots of fat but not burning energy, and the body thinks it needs to store energy," said Jorge Moscat, Ph.D., Sanford-Burnham professor. "It's a double whammy." Moscat led the study with collaborators at Helmholtz Zentrum München in Germany and the University of Cincinnati.

p62 and obesity

Moscat's team had previously produced mice that completely lack the p62 protein everywhere in their bodies. As a result, the animals were obese. They also had metabolic syndrome. In other words, as compared to mice with p62, mice lacking p62 weighed more, expended less energy, had diabetes and had a hyper-inflammatory response that's characteristic of obesity.

While those results showed that the lack of p62 leads to obesity, "we didn't know which tissue was responsible for these effects, because p62 was missing in all of them," Moscat said.

Some researchers believe that muscle tissue, where energy is expended, controls obesity. Others suspect the liver is a key player, or that the brain's appetite control center is most responsible for obesity.

But then there's fat itself—both white fat and brown fat. White fat is the type we think of as unwanted body fat. Brown fat, on the other hand, is beneficial because it burns calories. Many researchers now believe that brown fat somehow malfunctions in obesity, but the details are unclear.

p62 shifts the balance between white fat and brown fat

In their latest study, Moscat and colleagues set out to pinpoint 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. They weren't obese like the mice lacking p62 everywhere.

Then they made a mouse model lacking p62 only in their 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 ERK while activating another enzyme called p38. When p62 is missing, the enzyme p38 is less active in brown fat, while ERK is more active in white fat. As a result, Moscat said, p62 is "a master regulator" in normal fat metabolism.

According to Moscat, 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.

New methods for preventing or treating obesity, a major epidemic in the United States, are urgently needed. Drug therapies designed to minimize the intake of food have had limited success and also produce considerable side effects.

This study was funded by the National Institutes of Health - National Institute of Allergy and Infectious Diseases grant DK088107 and National Cancer Institute grants CA132847 and CA134530.

The study was co-authored by Timo D. Müller, Helmholtz Zentrum München, Technical University München; Sang Jun Lee, Sanford-Burnham; Martin Jastroch, Helmholtz Zentrum München, Technical University München; Dhiraj Kabra, Helmholtz Zentrum München, Technical University München; Kerstin Stemmer, Helmholtz Zentrum München, Technical University München; Michaela Aichler, Helmholtz Centre Munich; Bill Abplanalp, University of Cincinnati; Gayathri Ananthakrishnan, University of Cincinnati; Nakul Bhardwaj, University of Cincinnati; Sheila Collins, Sanford-Burnham; Senad Divanovic, University of Cincinnati College of Medicine; Max Endele, Helmholtz Center Munich-German Research Center for Environmental Health; Brian Finan, Helmholtz Zentrum München, Technical University München; Yuanqing Gao, University of Cincinnati; Kirk M. Habegger, University of Cincinnati; Jazzmin Hembree, University of Cincinnati; Kristy M. Heppner, University of Cincinnati; Susanna Hofmann, Helmholtz Centre Munich; Jenna Holland, University of Cincinnati; Daniela Küchler, Helmholtz Zentrum München, Technical University München; Maria Kutschke, Helmholtz Zentrum München, Technical University München; Radha Krishna, University of Cincinnati; Maarit Lehti, University of Cincinnati; Rebecca Oelkrug, Philipps Universität Marburg; Nickki Ottaway, University of Cincinnati; Diego Perez-Tilve, University of Cincinnati; Christine Raver, University of Cincinnati; Axel K. Walch, Helmholtz Centre Munich; Sonja C. Schriever, Helmholtz Zentrum München, Technical University München; John Speakman, Institute of Genetics and Developmental Biology, Beijing, University of Aberdeen; Yu-Hua Tseng, Joslin Diabetes Center, Harvard Medical School; Maria Diaz-Meco, Sanford-Burnham; Paul T. Pfluger, Helmholtz Zentrum München, Technical University München, University of Cincinnati; Jorge Moscat, Sanford-Burnham; and Matthias H. Tschöp, Helmholtz Zentrum München, Technical University München, University of Cincinnati.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, news, and events, please visit us at sanfordburnham.org.

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