Human C-reactive protein impedes entry of leptin into the CNS and attenuates its physiological actions in the CNS.

Defective central leptin signaling and the impaired leptin’s entry into the CNS represent two important aspects of leptin resistance in obesity. Herein we tested if circulating human CRP not only diminishes signaling of leptin within the CNS, but also impedes this adipokine’s access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore following peripheral infusion of human leptin, the CSF concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS to hCRP transgenic mice dramatically elevated the concentrations of human CRP in the CSF. Intracerebroventricular ( i.c.v ) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signaling by human leptin, ameliorated the effects of leptin on the expression of neuropeptide-Y, AgRP, POMC, and SOCS-3. Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin.