Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress

EMBO Molecular Medicine

Toru Hosoi¹  Rie Yamaguchi¹  Kikuko Noji¹  Suguru Matsuo¹  Sachiko Baba¹  Keisuke Toyoda¹  Takahiro Suezawa¹  Takaaki Kayano¹  Shinpei Tanaka² 

[1] Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan;School of Integrated Arts & Sciences, Hiroshima University, Higashi-Hiroshima, Japan

关键词: STAT3;    aldehyde dehydrogenase;    nonsteroidal anti‐inflammatory drug;   

DOI  :  10.1002/emmm.201303227

来源: Wiley

【 摘 要 】

Abstract

Endoplasmic reticulum (ER) stress, caused by the accumulation of unfolded proteins, is involved in the development of obesity. We demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited chaperone activity, which reduced protein aggregation and alleviated ER stress-induced leptin resistance, characterized by insensitivity to the actions of the anti-obesity hormone leptin. This result was further supported by flurbiprofen attenuating high-fat diet-induced obesity in mice. The other NSAIDs tested did not exhibit such effects, which suggested that this anti-obesity action is mediated independent of NSAIDs. Using ferriteglycidyl methacrylate beads, we identified aldehyde dehydrogenase as the target of flurbiprofen, but not of the other NSAIDs. These results suggest that flurbiprofen may have unique pharmacological properties that reduce the accumulation of unfolded proteins and may represent a new class of drug for the fundamental treatment of obesity.

Synopsis

Through targeting aldehyde dehydrogenase, flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), is shown to attenuate protein misfolding, endoplasmic reticulum stress and subsequent development of leptin resistance, overall reducing obesity in mice.

• Flurbiprofen exhibited chaperone activity and alleviated ER stress-induced leptin resistance.
• Flurbiprofen attenuated high-fat diet-induced obesity in mice.
• Aldehyde dehydrogenase was the target of flurbiprofen.
• Flurbiprofen may have pharmacological properties in treating obesity by reducing the accumulation of unfolded proteins.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.