Systemic administration of leptin decreases plasma corticosterone levels: role of hypothalamic norepinephrine

Leptin, an adipocyte-derived hormone, is known to regulate a variety of neuroendocrine functions. It inhibits the hypothalamo-pituitary-adrenal axis (HPA) in several animal models, however, the exact mechanism by which it does so is not known. Since norepinephrine (NE) is a key regulator of the HPA axis, we hypothesized that leptin could suppress HPA activity by decreasing NE levels. To study this, we implanted adult male Sprague-Dawley rats with both a push-pull cannula in the paraventricular nucleus (PVN) and a catheter in the jugular vein. Animals were treated with either 0 or 100 microg or 500 microg of recombinant rat leptin (Lep). Push-pull perfusion was performed from 1000-1600 h. Perfusate samples were collected every 30 min and analyzed for NE levels using HPLC-EC. Blood samples were collected every 60 min and analyzed for corticosterone (CS) levels. To further understand the role of NE in this phenomenon animals were treated with either an alpha1-adrenergic agonist, phenylephrine (PHE; 0.5 mg/kg BW), an alpha2-adrenergic agonist, clonidine (CLON; 0.6 mg/kg BW), or a beta-adrenergic agonist, isoproterenol (ISO; 0.2 mg/kg BW) alone or in combination with 500 microg of Lep. Pre-treatment and hourly post-treatment blood samples were collected, plasma was separated and analyzed for CS levels. Leptin administration decreased NE release in the PVN significantly by 30 min (p<0.05). It also significantly reduced plasma CS levels at 240 and 300 min (p<0.05). Administration of either PHE or CLON in combination with leptin prevented the leptin-induced decrease in CS. In contrast, administration of ISO along with leptin did not prevent the leptin-induced decrease in CS. These results indicate that leptin decreases hypothalamic NE and plasma CS and that this effect is most probably mediated through alpha-adrenergic receptors.