TY - JOUR T1 - Endoplasmic Reticulum Stress Induces Leptin Resistance JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1610 LP - 1619 DO - 10.1124/mol.108.050070 VL - 74 IS - 6 AU - Toru Hosoi AU - Miyako Sasaki AU - Tsuyoshi Miyahara AU - Chie Hashimoto AU - Suguru Matsuo AU - Michiko Yoshii AU - Koichiro Ozawa Y1 - 2008/12/01 UR - http://molpharm.aspetjournals.org/content/74/6/1610.abstract N2 - 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 NH2-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. The American Society for Pharmacology and Experimental Therapeutics ER -