title: Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy.
abstract: Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 microg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.
authors.affiliation: Obesity Research Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Madiehe
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.forename: C
authors.initials: C
authors.lastname: White
authors.forename: H D
authors.initials: HD
authors.lastname: Braymer
authors.forename: G A
authors.initials: GA
authors.lastname: Bray
authors.forename: D A
authors.initials: DA
authors.lastname: York
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics; D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects; D000315:Adrenalectomy; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D002149:Energy Intake / Q000187:drug effects; D004822:Epididymis; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007263:Infusions, Parenteral; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000209:Acute-Phase Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D007328:Insulin; D020738:Leptin; D011506:Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D003345:Corticosterone