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Molecular Pharmacology

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Research ArticleArticle

Endoplasmic Reticulum Stress Induces Leptin Resistance

Toru Hosoi, Miyako Sasaki, Tsuyoshi Miyahara, Chie Hashimoto, Suguru Matsuo, Michiko Yoshii and Koichiro Ozawa
Molecular Pharmacology December 2008, 74 (6) 1610-1619; DOI: https://doi.org/10.1124/mol.108.050070
Toru Hosoi
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Miyako Sasaki
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Tsuyoshi Miyahara
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Chie Hashimoto
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Suguru Matsuo
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Michiko Yoshii
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Koichiro Ozawa
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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 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.

Footnotes

  • This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by the Institute of Laboratory Animal Science.

  • ABBREVIATIONS: JAK, janus kinase; ER, endoplasmic reticulum; STAT, signal transducer and activator of transcription; JNK, c-Jun NH2-terminal kinase; PTP1B, protein tyrosine phosphatase 1B; SOCS3, suppressors of cytokine signaling 3; UPR, unfolded protein response; GRP78, glucose regulated protein 78; CHOP, CCAAT/enhancer-binding protein homologous protein; ERK, extracellular signal-regulated kinase; HEK, human embryonic kidney; siRNA, short interfering RNA; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Tm, tunicamycin; Tg, thapsigargin; 4-PBA, 4-phenyl butyric acid; RNAi, RNA interference; Bre, brefeldin A.

    • Received June 26, 2008.
    • Accepted August 28, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (6)
Molecular Pharmacology
Vol. 74, Issue 6
1 Dec 2008
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Research ArticleArticle

Endoplasmic Reticulum Stress Induces Leptin Resistance

Toru Hosoi, Miyako Sasaki, Tsuyoshi Miyahara, Chie Hashimoto, Suguru Matsuo, Michiko Yoshii and Koichiro Ozawa
Molecular Pharmacology December 1, 2008, 74 (6) 1610-1619; DOI: https://doi.org/10.1124/mol.108.050070

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Research ArticleArticle

Endoplasmic Reticulum Stress Induces Leptin Resistance

Toru Hosoi, Miyako Sasaki, Tsuyoshi Miyahara, Chie Hashimoto, Suguru Matsuo, Michiko Yoshii and Koichiro Ozawa
Molecular Pharmacology December 1, 2008, 74 (6) 1610-1619; DOI: https://doi.org/10.1124/mol.108.050070
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