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Title: PPARα-Mediated Positive-Feedback Loop Contributes to Cold Exposure Memory
Authors: Alfaqaan, Soaad
Yoshida, Tomoki  kyouindb  KAKEN_id
Imamura, Hiromi  kyouindb  KAKEN_id  orcid (unconfirmed)
Tsukano, Chihiro  kyouindb  KAKEN_id  orcid (unconfirmed)
Takemoto, Yoshiji  kyouindb  KAKEN_id  orcid (unconfirmed)
Kakizuka, Akira  kyouindb  KAKEN_id
Author's alias: 吉田, 有希
今村, 博臣
塚野, 千尋
竹本, 佳司
垣塚, 彰
Issue Date: 14-Mar-2019
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 9
Thesis number: 4538
Abstract: Fluctuations in food availability and shifts in temperature are typical environmental changes experienced by animals. These environmental shifts sometimes portend more severe changes; e.g., chilly north winds precede the onset of winter. Such telltale signs may be indicators for animals to prepare for such a shift. Here we show that HEK293A cells, cultured under starvation conditions, can “memorize” a short exposure to cold temperature (15 °C), which was evidenced by their higher survival rate compared to cells continuously grown at 37 °C. We refer to this phenomenon as “cold adaptation”. The cold-exposed cells retained high ATP levels, and addition of etomoxir, a fatty acid oxidation inhibitor, abrogated the enhanced cell survival. In our standard protocol, cold adaptation required linoleic acid (LA) supplementation along with the activity of Δ-6-desaturase (D6D), a key enzyme in LA metabolism. Moreover, supplementation with the LA metabolite arachidonic acid (AA), which is a high-affinity agonist of peroxisome proliferator-activated receptor-alpha (PPARα), was able to underpin the cold adaptation, even in the presence of a D6D inhibitor. Cold exposure with added LA or AA prompted a surge in PPARα levels, followed by the induction of D6D expression; addition of a PPARα antagonist or a D6D inhibitor abrogated both their expression, and reduced cell survival to control levels. We also found that the brief cold exposure transiently prevents PPARα degradation by inhibiting the ubiquitin proteasome system, and starvation contributes to the enhancement of PPARα activity by inhibiting mTORC1. Our results reveal an innate adaptive positive-feedback mechanism with a PPARα-D6D-AA axis that is triggered by a brief cold exposure in cells. “Cold adaptation” could have evolved to increase strength and resilience against imminent extreme cold temperatures.
Rights: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
DOI(Published Version): 10.1038/s41598-019-40633-3
PubMed ID: 30872768
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