RT Journal Article
SR Electronic
T1 Endoplasmic Reticulum Stress Induces Leptin Resistance
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1610
OP 1619
DO 10.1124/mol.108.050070
VO 74
IS 6
A1 Hosoi, Toru
A1 Sasaki, Miyako
A1 Miyahara, Tsuyoshi
A1 Hashimoto, Chie
A1 Matsuo, Suguru
A1 Yoshii, Michiko
A1 Ozawa, Koichiro
YR 2008
UL http://molpharm.aspetjournals.org/content/74/6/1610.abstract
AB 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