Identification and expression analysis of leptin-regulated immediate early response and late target genes

W Waelput, A Verhee, D Broekaert, S Eyckerman, J Vandekerckhove, J H Beattie, J Tavernier

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54 Citations (Scopus)

Abstract

Using PC12 cells as an in vitro model system, we have identified a series of transcripts induced through activation of the leptin receptor. On the basis of kinetic studies, two distinct gene sets could be discerned: signal transducer and activator of transciption-3 (STAT-3), suppressor of cytokine signalling-3 (SOCS-3), MT-II (metallothionein-II), the serine/threonine kinase fibroblast-growth-factor-inducible kinase (Fnk) and modulator recognition factor (MRF-1), which are immediate early response genes, and pancreatitis-associated protein I (PAP I), squalene epoxidase, uridine diphosphate glucuronosyltransferase and annexin VIII, which are late induced target genes. At late time points a strong co-stimulation with beta-nerve growth factor or with the adenylate cyclase activator forskolin was observed. To assess the validity of the PC12-cell model system, we examined the effect of leptin administration on the gene transcription of STAT-3, MT-II, Fnk and PAP I in vivo. Leptin treatment of leptin-deficient ob/ob mice increased the STAT-3, SOCS-3, MT-II and Fnk mRNA, and MT-I protein levels in liver, whereas, in jejunum, expression of PAP I mRNA was down-regulated. Furthermore, administration of leptin to starved wild-type mice enhanced the expression of MT-II and Fnk mRNA in liver, but decreased MT-II and PAP I mRNA expression in jejunum. These findings may help to explain the obese phenotype observed in some colonies of MT-I- and MT-II-null mice and/or the observation that leptin protects against tumour-necrosis-factor toxicity in vivo.

Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalBiochemical Journal
Volume348
Publication statusPublished - 15 May 2000

Keywords

  • forskolin
  • gene induction
  • metallothionein
  • PC12 cells
  • representational difference analysis
  • REPRESENTATIONAL DIFFERENCE ANALYSIS
  • MESSENGER-RNA EXPRESSION
  • METALLOTHIONEIN-II GENES
  • IN-SITU HYBRIDIZATION
  • OBESE GENE
  • BODY-WEIGHT
  • PERIPHERAL-TISSUES
  • NEUROPEPTIDE-Y
  • DIABETIC MICE
  • DB/DB MICE

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