Increased E4 activity in mice leads to ubiquitin-containing aggregates and degeneration of hypothalamic neurons resulting in obesity

Etsuo Susaki, Chie Kaneko-Oshikawa, Keishi Miyata, Mitsuhisa Tabata, Tetsuya Yamada, Yuichi Oike, Hideki Katagiri, Keiichi Nakayama

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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.

Original languageEnglish
Pages (from-to)15538-15547
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number20
DOIs
Publication statusPublished - May 14 2010

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Nerve Degeneration
Ubiquitin
Neurodegenerative diseases
Neurons
Obesity
Brain
Transgenic Mice
Peptide Elongation Factors
Public health
Pathology
Medical problems
Neurodegenerative Diseases
Animals
Deposits
Cells
Energy Metabolism
Cultured Cells
Proteins
Animal Models
Public Health

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Increased E4 activity in mice leads to ubiquitin-containing aggregates and degeneration of hypothalamic neurons resulting in obesity. / Susaki, Etsuo; Kaneko-Oshikawa, Chie; Miyata, Keishi; Tabata, Mitsuhisa; Yamada, Tetsuya; Oike, Yuichi; Katagiri, Hideki; Nakayama, Keiichi.

In: Journal of Biological Chemistry, Vol. 285, No. 20, 14.05.2010, p. 15538-15547.

Research output: Contribution to journalArticle

Susaki, Etsuo ; Kaneko-Oshikawa, Chie ; Miyata, Keishi ; Tabata, Mitsuhisa ; Yamada, Tetsuya ; Oike, Yuichi ; Katagiri, Hideki ; Nakayama, Keiichi. / Increased E4 activity in mice leads to ubiquitin-containing aggregates and degeneration of hypothalamic neurons resulting in obesity. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 20. pp. 15538-15547.
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