Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the de velopment of many forms of obesity in rodents, including those that are lep tin or leptin receptor deficient. Obesity is associated with hyperleptinemi a and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinas e (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 mug icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-P CR, Western blots, and mobility shift assays was used to evaluate the lepti n signaling pathway in whole hypothalami from sham-operated, ADX and cortic osterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increa sed the expression of leptin receptor mRNA, increased STAT-3 mRNA and prote in levels, induced constitutive STAT-3 phosphorylation and DNA binding acti vity, 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 d ecreased NPY mRNA expression, but their combination did not further decreas e NPY mRNA. Corticosterone supplementation of ADX rats partially reversed m any of these effects. In conclusion, ADX through activation of STAT-3 and i nhibition 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.