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Leptin is an anti-obesity protein and its action is mainly mediated by the activation of its Ob-R receptor in neuronal cells. The inability of leptin to induce activation of its specific signaling pathways, especially under endoplasmic reticulum stress, leads to the leptin resistance observed in obesity. The present study examined the effect of homocysteine on leptin signaling in SH-SY5Y neuroblastoma cells expressing the leptin receptor Ob-Rb. Phosphorylation of the signal transducer and activator of transcription (STAT3) and leptin-induced STAT3 transcriptional activity were significantly inhibited by homocysteine treatment. These effects may be specific to homocysteine and to the leptin pathway, as other homocysteine-related compounds, namely methionine and cysteine, have weak effect on leptin-induced inhibition of STAT3 phosphorylation, and homocysteine has no impact on IL-6-induced activation of STAT3. The direct effect of homocysteine on leptin-induced Ob-R activation, analyzed by Ob-R BRET biosensor to monitor Ob-R oligomerization and conformational change, suggested that homocysteine treatment does not affect early events of leptin-induced Ob-R activation. Instead, we found that, unlike methionine or cysteine, homocysteine increases the expression of the endoplasmic reticulum (ER) stress response gene, a homocysteine-sensitive ER resident protein. These results suggest that homocysteine may induce neuronal resistance to leptin by suppressing STAT3 phosphorylation downstream of the leptin receptor via ER stress.<\/jats:p>","DOI":"10.1371\/journal.pone.0278965","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T18:53:25Z","timestamp":1670957605000},"page":"e0278965","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress"],"prefix":"10.1371","volume":"17","author":[{"given":"Arini Isnani","family":"Preninka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Kuriya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyosuke","family":"Yazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1887-4078","authenticated-orcid":true,"given":"Michiko","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhki","family":"Yanase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Jockers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Dam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4831-487X","authenticated-orcid":true,"given":"Toru","family":"Hosoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,13]]},"reference":[{"key":"pone.0278965.ref001","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1038\/srep07096","article-title":"Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells","volume":"4","author":"M Thon","year":"2014","journal-title":"Sci Rep"},{"issue":"13","key":"pone.0278965.ref002","doi-asserted-by":"crossref","first-page":"6231","DOI":"10.1073\/pnas.93.13.6231","article-title":"Defective STAT signaling by the leptin receptor in diabetic mice","volume":"93","author":"N Ghilardi","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0278965.ref003","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1124\/mol.108.050070","article-title":"Endoplasmic reticulum stress induces leptin resistance","volume":"74","author":"T Hosoi","year":"2008","journal-title":"Mol Pharmacol"},{"issue":"5","key":"pone.0278965.ref004","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nn1454","article-title":"Molecular and anatomical determinants of central leptin resistance","volume":"8","author":"H M\u00fcnzberg","year":"2005","journal-title":"Nat Neurosci"},{"issue":"4","key":"pone.0278965.ref005","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S1097-2765(00)80062-3","article-title":"Identification of SOCS-3 as a potential mediator of central leptin resistance","author":"C Bj\u00f8rbaek","year":"1998","journal-title":"Mol Cell"},{"key":"pone.0278965.ref006","doi-asserted-by":"crossref","first-page":"09","DOI":"10.1016\/S0303-7207(02)00178-8","article-title":"Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line","volume":"195","author":"W Kaszubska","year":"2002","journal-title":"Mol Cell Endocrinol"},{"issue":"422","key":"pone.0278965.ref007","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.bbrc.2012.05.048","article-title":"Endoplasmic reticulum stress and the on site function of resident PTP1B","author":"D. 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