TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus

Kazuhito Sai, Sho Morioka, Giichi Takaesu, Nagendran Muthusamy, H. Troy Ghashghaei, Hiroshi Hanafusa, Kunihiro Matsumoto, Jun Ninomiya-Tsuji

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases, including metabolic disorders. TAK1 (also known as MAP3K7) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family and is activated by a diverse set of inflammatory stimuli. Here, we demonstrate that TAK1 regulates ER stress and metabolic signaling through modulation of lipid biogenesis. We found that deletion of Tak1 increased ER volume and facilitated ER-stress tolerance in cultured cells, which was mediated by upregulation of sterol-regulatory-element-binding protein (SREBP)- dependent lipogenesis. In the in vivo setting, central nervous system (CNS)-specific Tak1 deletion upregulated SREBP-target lipogenic genes and blocked ER stress in the hypothalamus. Furthermore, CNS-specific Tak1 deletion prevented ER-stress-induced hypothalamic leptin resistance and hyperphagic obesity under a high-fat diet (HFD). Thus, TAK1 is a crucial regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions.

Original languageEnglish (US)
Pages (from-to)1855-1865
Number of pages11
JournalJournal of Cell Science
Issue number9
StatePublished - May 1 2016
Externally publishedYes


  • Endoplasmic reticulum stress
  • Hypothalamus
  • Leptin
  • Obesity
  • TAK1

ASJC Scopus subject areas

  • Cell Biology


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