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J Cell Sci. 2016 May 1;129(9):1855-65. doi: 10.1242/jcs.180505. Epub 2016 Mar 16.

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

Author information

1
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
2
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
3
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
4
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
5
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA Jun_Tsuji@ncsu.edu.

Abstract

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.

KEYWORDS:

Endoplasmic reticulum stress; Hypothalamus; Leptin; Obesity; TAK1

PMID:
26985063
PMCID:
PMC4893799
DOI:
10.1242/jcs.180505
[Indexed for MEDLINE]
Free PMC Article

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