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.Subject Categories Metabolism; Pharmacology & Drug Discovery

Increasing evidence indicates that endoplasmic reticulum stress (ER stress) is involved in the development of metabolic syndrome. However, pharmacological treatments targeting ER stress are not well understood. In the present study, we found that fluvoxamine, a selective serotonin reuptake inhibitor used for depression, can attenuate ER stress-induced “leptin resistance,” i.e., insensitivity to the anti-obesity hormone leptin. Treatment with tunicamycin, an ER stress-inducing reagent, caused cell death which was significantly inhibited by fluvoxamine. Leptin activates JAK2–STAT3 signaling. ER stress caused an impairment of leptin-induced STAT3 phosphorylation which was reversed by fluvoxamine. Fluvoxamine would be a novel leptin-sensitizing drug, which targets ER stress.

Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) and signal transducer and activator of transcription 5 (STAT5) in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein and glucose regulated protein 78 induction, indicating the activation of unfolded protein responses (UPR). Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells.