title: TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus.
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.
authors.affiliation: 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.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Sai
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
authors.forename: Sho
authors.initials: S
authors.lastname: Morioka
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
authors.forename: Nagendran
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
authors.forename: H Troy
authors.initials: HT
authors.lastname: Ghashghaei
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hanafusa
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA Jun_Tsuji@ncsu.edu.
authors.forename: Jun
authors.identifier: 0000-0002-5584-0176
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D006963:Hyperphagia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004041:Dietary Fats; D020738:Leptin; D020930:MAP Kinase Kinase Kinases; D051779:Sterol Regulatory Element Binding Proteins; D000099151:MAP Kinase Kinase Kinase 7
keywords: Endoplasmic reticulum stress; Hypothalamus; Leptin; Obesity; TAK1