title: Endoplasmic reticulum stress induces leptin resistance.
abstract: Leptin is an important circulating signal for inhibiting food intake and body weight gain. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are poorly understood. Increasing evidence has suggested that stress signals, which impair endoplasmic reticulum (ER) function, lead to an accumulation of unfolded proteins, which results in ER stress. In the present study, we hypothesized that ER stress is involved in leptin resistance. Tunicamycin, thapsigargin, or brefeldin A was used to induce ER stress. The activation status of leptin signals was measured by Western blotting analysis using a phospho-(Tyr705) signal transducer and activator of transcription 3 (STAT3) antibody. We observed that ER stress markedly inhibited leptin-induced STAT3 phosphorylation. In contrast, ER stress did not affect leptin-induced c-Jun NH(2)-terminal kinase activation. These results suggest that ER stress induces leptin resistance. ER stress-induced leptin resistance was mediated through protein tyrosine phosphatase 1B but not through suppressors of cytokine signaling 3. It is noteworthy that a chemical chaperone, which could improve the protein-folding capacity, reversed ER stress-induced leptin resistance. Moreover, homocysteine, which induces ER stress, caused leptin resistance both in vitro and in vivo. Together, these findings suggest that the pathological mechanism of leptin resistance is derived from ER stress.
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoi
authors.forename: Miyako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyahara
authors.forename: Chie
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Suguru
authors.initials: S
authors.lastname: Matsuo
authors.forename: Michiko
authors.initials: M
authors.lastname: Yoshii
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ozawa