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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.

SUBMITTER: Hosoi T

PROVIDER: S-EPMC3958308 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Hosoi Toru T Yamaguchi Rie R Noji Kikuko K Matsuo Suguru S Baba Sachiko S Toyoda Keisuke K Suezawa Takahiro T Kayano Takaaki T Tanaka Shinpei S Ozawa Koichiro K

EMBO molecular medicine 20140113 3

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 i ...[more]

PMID: 24421337

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Project description:BackgroundExtracellular accumulation of amyloid ?-peptide (A?) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against A? neurotoxicity in AD remains unknown.MethodsIn the present study, the characteristic expressions of MANF in A?1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following A?1-42 exposure were also investigated.ResultsThe results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and A?1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against A?1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated A?1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2?, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following A?1-42 exposure, whereas knockdown of MANF has the opposite effect.ConclusionsThese findings demonstrate that MANF may exert neuroprotective effects against A?-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.

Dataset Information

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

Publications

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

Similar Datasets

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