Adult-onset obesity seen in mice when gene ubiquitin disrupted

Texas and California scientists who disrupted one type of the gene ubiquitin (Ubb) in mice observed neuronal death in the hypothalamus, impaired control of energy balance and adult-onset obesity in the rodents.

The study, which hints at a method to treat obesity and neurodegeneration, is described in this week's online Early Edition of the Proceedings of the National Academy of Sciences, U.S.A.

“Ubiquitin is a small protein in the cell that marks unwanted proteins for destruction,” said research co-author Xin-Yun Lu, Ph.D., assistant professor in the Department of Pharmacology at The University of Texas Health Science Center at San Antonio. “This study shows that the deletion of a ubiquitin gene, Ubb, caused neurodegeneration in the hypothalamus, an important brain area for maintaining energy homeostasis. Mice with the Ubb gene deficiency have normal appetite but store fat more efficiently.”

Dr. Lu and a graduate student in her laboratory, Jacob C. Garza, collaborated on the project with colleagues from Stanford University.

Among the study findings:

• Adult mice with no functioning copies of the Ubb gene were fatter over the course of their life span than adult mice with one or both functional Ubb copies. At 1 month of age, the Ubb-deficient group had 20 percent fat content (fat as percentage of body weight) compared to 18 percent in the Ubb-functional group. At 4-7 months of age, the Ubb-deficient mice had 45 percent fat content compared to 33 percent in the Ubb-functional group. By 10 months of age, the Ubb-deficient mice had 52 percent fat content compared to 37 percent in the Ubb-functional group.
• While counts of hypothalamic neurons showed no difference in 1-month-old mice in both groups, by 3 months of age the rodents in the Ubb-deficient group had 30 percent fewer hypothalamic neurons than did their healthy peers.

Alan Frazer, Ph.D., chair of the Department of Pharmacology at the UT Health Science Center, said the results are “both novel and important. They indicate that decreasing ubiquitin availability leads to neuronal cell death in the brain and causes obesity. This finding may lead to the development of novel therapeutic approaches to treat these disorders.”

Dr. Lu is an affiliated member of the Sam and Ann Barshop Institute for Longevity and Aging Studies at the UT Health Science Center.

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