THE SUBFORNICAL ORGAN AND AREA POSTREMA MEDIATE THE CENTRAL EFFECTS OF CIRCULATING LEPTIN
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Leptin is an adipokine that acts centrally to regulate feeding behaviour, energy expenditure and autonomic function via activation of its receptor (ObRb) in nuclei in the central nervous system (CNS). This thesis investigates the involvement of two sensory circumventricular organs (CVOs), the subfornical organ (SFO) and area postrema (AP), in mediating the central effects of leptin using a variety of experimental approaches. We first show that acute electrical stimulation of the SFO elicits feeding in satiated rats, supporting a role for this specialized CNS structure in the control of food intake. We then demonstrate, using RT-PCR, the presence of ObRb mRNA in SFO and, using whole cell current clamp electrophysiology, reveal that leptin influences the excitability of individual SFO neurons, causing both excitatory and inhibitory responses. Furthermore, we find that leptin activates the same SFO neurons activated by amylin. Given the association between obesity and hypertension and the well-established role of the SFO in cardiovascular regulation, we show that leptin microinjection into the SFO decreases blood pressure in young rats, effects that are abolished in leptin-resistant, diet induced obese rats, suggesting that leptin-insensitivity in the SFO of obese, leptin-resistant, individuals may contribute to obesity-related hypertension. Our studies also show that the medullary AP expresses ObRb and that leptin influences the excitability of AP neurons. Furthermore, we show that leptin and amylin act on the same subpopulation of neurons in the AP. Finally, our preliminary AP/SFO lesion studies reveal that animals with these lesions exhibit a profound decrease in body weight and food intake and no longer exhibit decreases in body weight in response to peripheral leptin administration. In summary, the data presented in this thesis suggest the SFO and AP to be important in body weight homeostasis and in mediating the central effects of leptin. In addition, these areas appear to be important in the integration of multiple signals derived from peripheral sources. Furthermore, the fact that the SFO appears to be involved in leptin effects on both energy balance and cardiovascular regulation attest to the integrative nature of the SFO in the control of diverse physiological functions.