title: Excessive nitric oxide attenuates leptin-mediated signal transducer and activator of transcription 3 activation.
abstract: The mechanisms of leptin resistance observed in most cases of human obesity are poorly understood. Therefore, we evaluated the effects of nitric oxide (NO) on the leptin-induced activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways and on the leptin receptor (LEPR) expression using SH-SY5Y cells. Here, we show that the NO donor spermine/NONOate inhibited leptin-induced activation of STAT3 in vitro. The inhibition of leptin-mediated STAT3 phosphorylation caused by excessive NO was partially prevented by a sulfhydryl reducing agent, ascorbic acid. Cellular experiments show that reduced expression of long form leptin receptor (LEPR-b) and STAT3 protein instability induced by NO may be mechanisms of the NO-mediated inhibition of leptin-STAT3 signaling. We also present data showing that the hypothalamic NO content of high-fat (HF)-diet-induced obese mice was higher than that of control mice; this is likely caused by decreased caveolin-1 expression and increased nNOS expression induced by HF diet over 19 weeks. Concurrently with the overproduction of NO, the decrease of hypothalamic LEPR-b in obese mice also supports these in vitro data. Combined results suggest that excess of NO can induce the attenuation of leptin-mediated STAT3 activation through reduced expression of LEPR-b mRNA and instability of STAT3 protein at least in part. Furthermore, our in vivo data indicate that long-term HF diet induces hypothalamic overproduction of NO, which may be related with leptin insensitivity. However, further study is required to warrant direct in vivo evidence of a causal relationship between endogenous excess of hypothalamic NO and central leptin resistance.
authors.affiliation: Department of Pharmacology and Medicinal Toxicology Research Center, Inha Research Institute for Medical Sciences, Center for Advanced Medical Education, Inha University, College of Medicine by BK-21 Project, South Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Jang
authors.forename: Chang-Shin
authors.initials: CS
authors.lastname: Park
authors.forename: Sung-Keun
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae-Eun
authors.initials: JE
authors.lastname: Pie
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D004041:Dietary Fats / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000737:chemistry / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D051242:Caveolin 1; D004041:Dietary Fats; C515448:LEPR protein, human; D020738:Leptin; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C515447:leptin receptor, mouse; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D001205:Ascorbic Acid