2016 journal article

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

JOURNAL OF CELL SCIENCE, 129(9), 1855–1865.

By: K. Sai n, S. Morioka n, G. Takaesu n, N. Muthusamy, H. Ghashghaei n, H. Hanafusa*, K. Matsumoto*, J. Ninomiya-Tsuji n

author keywords: TAK1; Endoplasmic reticulum stress; Leptin; Hypothalamus; Obesity
Source: Web Of Science
Added: August 6, 2018

Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases including metabolic disorders. TAK1 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 proteins (SREBPs)-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 high fat diet (HFD). Thus, TAK1 is a critical regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions.