Fluvoxamine Attenuated Endoplasmic Reticulum Stress-Induced Leptin Resistance

Abstract

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.

Drug targeting of leptin resistance

“…Hosoi et al [179] have demonstrated that the inhibitor of serotonin uptake, fluvoxamine, attenuated ER stress-induced leptin resistance, increasing STAT3 phosphorylation, and reducing food consumption in mice. Moreover, it has been shown that also the gaseous transmitter carbon monoxide was able to revert leptin resistance induced by thapsigargin or tunicamycin in human cells [180].…”

“…Improvement of insulin signaling and glucose homeostasis. Increase in STAT3 phosphorylation [177][178][179][181][182][183][184].…”

New Pharmacological Perspectives for the Leptin Receptor in the Treatment of Obesity

“…4-PBA and TUDCA treatment successfully alleviate hypothalamic ER stress and restore leptin responsiveness in high-fat diet-fed mice by reducing food consumption along with body weight ( 65 ). Hosoi et al has reported that fluvoxamine, a selective serotonin reuptake inhibitor prescribed for the treatment of depression, which binds the ER receptor Sigma1, is able to alleviate ER stress and reverse leptin resistance in cells, and to decrease food intake in mice ( 171 ). Recently, flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), was shown to reduce ER stress, to attenuate leptin resistance and to reduce the body weight of HFD obese mice ( 172 , 173 ).…”

Hypothalamic ER stress: A bridge between leptin resistance and obesity

“…Recent studies have further tested the ability of other clinical compounds in the resolution of ER stress. Fluvoxamine, a selective serotonin reuptake inhibitor primarily used for a number of anxiety and depressive disorders, attenuates ER stress‐induced leptin resistance in neuronal cell lines and mice [102]. Flurbiprofen is a phenylalkanoic acid derivative of non‐steroidal anti‐inflammatory drugs which is prescribed to treat arthritis.…”