title: Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress.
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.
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoi
authors.forename: Rie
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Kikuko
authors.initials: K
authors.lastname: Noji
authors.forename: Suguru
authors.initials: S
authors.lastname: Matsuo
authors.forename: Sachiko
authors.initials: S
authors.lastname: Baba
authors.forename: Keisuke
authors.initials: K
authors.lastname: Toyoda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suezawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kayano
authors.forename: Shinpei
authors.initials: S
authors.lastname: Tanaka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059305:Diet, High-Fat; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005480:Flurbiprofen / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000209:etiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020738:Leptin; D034741:RNA, Small Interfering; D005480:Flurbiprofen; D000444:Aldehyde Dehydrogenase