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Abstract
Obesity has become a serious worldwide public health problem. Although neural degeneration in specific brain regions has been suggested to contribute to obesity phenotype in humans, a causal relationship between these two conditions has not been demonstrated experimentally. We now show that E4B (also known as UFD2a), a mammalian ubiquitin chain elongation factor (E4), induces the formation of intracellular aggregates positive for ubiquitin and the adaptor protein p62 when overexpressed in cultured cells or the brain. Mice transgenic for E4B manifested neural degeneration in association with aggregate formation, and they exhibited functional impairment specifically in a subset of hypothalamic neurons that regulate food intake and energy expenditure, resulting in development of hyperphagic obesity and related metabolic abnormalities. The neural pathology of E4B transgenic mice was similar to that of human neurodegenerative diseases associated with the formation of intracellular ubiquitin-positive deposits, indicating the existence of a link between such diseases and obesity and related metabolic disorders. Our findings thus provide experimental evidence for a role of hypothalamic neurodegeneration in obesity, and the E4B transgenic mouse should prove to be a useful animal model for studies of the relationship between neurodegenerative diseases and obesity.
Highlights
Insight into signaling pathways that control food intake and energy homeostasis in humans has been provided by animal models of obesity associated with diet manipulation, spontaneous mutation of key molecules, transgenesis, or gene knockout, or physical intervention (1)
A, Neuro2A cells were transfected with expression vectors encoding Myc epitope-tagged wild-type (WT) or ⌬U mutant forms of E4B, or with the corresponding empty vector (Mock), for 24 h, after which the cells were subjected to immunofluorescence analysis with antibodies to polyubiquitin and the Myc epitope
B, Neuro2A cells transfected with the expression vector for Myc epitope-tagged WT E4B as in A were subjected to immunofluorescence analysis with antibodies to polyubiquitin and p62
Summary
Huntington disease and spinocerebellar ataxias are characterized by the formation of intracellular protein aggregates in neurons and neuronal loss. These diseases have been linked to the ubiquitin-proteasome system by the observation that the intracellular aggregates are recognized by antibodies to ubiquitin. The multifunctional adaptor protein p62, which contains domains that mediate protein-protein interaction, was recently shown to associate with the ubiquitin-positive aggregates and promote their formation (19 –23). This protein is used as a marker for cellular ubiquitin aggregates. Myc tions was performed with antibodies to the Myc epitope (9E10), polyubiquitin (FK2), p62 (28), glial fibrillary acidic protein
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