Our overall goal is determine how endocrine and sensory information associated with altered states of nutrition is relayed to the reproductive system. This proposal is based upon our observation that the metabolic hormone, leptin, administered alone during food restriction maintains pulsatile LH secretion. Conditions which limit food or metabolic fuels can profoundly effect the reproductive axis. In this proposal, we test the hypothesis that these compromised metabolic conditions are """"""""sensed"""""""" by the brain as a """"""""stress"""""""" and it is this """"""""stress"""""""" that leads to an inhibition in LH pulses. According to this hypothesis, leptin acts by inhibiting this """"""""stress"""""""" reaction via brain sites thereby maintaining pulsatile LH secretion.
In Specific aim one, we will determine if fasting activates the stress axis concurrently with the inhibition of pulsatile LH secretion and if leptin administration during the fasting period blocks the stress activation as well as LH pulse inhibition. Additionally in this aim, we determine if CRH neurons in the paraventricular nucleus (PVN) as well as in other non-PVN CRH sites are regulated by fasting and if leptin reverses this regulation.
In Specific aim two, we will determine if acute reductions in brain leptin (immunoneutralization) activate the stress axis while inhibiting pulsatile LH secretion. It also determines if these neuroendocrine changes are mediated by the stress peptide, corticotropin releasing hormone, CRH. Further in this aim, we will identify those neurons activated by reduced brain leptin (cfos activation) in an attempt to identify those cells responding to the reduced availability of this metabolic hormone. The last study in this aim, identifies the neuropeptide phenotype of cfos activated cells due to reductions in brain leptin. Using this anatomical data together with the data on CRH, we expect to identify neuropeptide systems responding to reduced brain leptin and potential mediators of the neuroendocrine changes.
In Specific aim three, we will use anatomical tract tracing methods and receptor mRNA colocalization studies to determine if CRH (or other suggested leptin sensitive neuropeptides) project directly or indirectly to GnRH neurons. This project is relevant to human health because it addresses the underlying mechanisms and anatomical pathways that are regulated by the fat hormone leptin, a hormone critical to the proper functioning of many neuroendocrine systems. This work should help explain the basis for disruption of neuroendocrine functions in several metabolic disorders as well as provide insight into understanding the endocrine complexities observed in several animal models of obesity.
| Seasholtz, Audrey F; Ohman, Miina; Wardani, Amale et al. (2009) Corticotropin-releasing hormone receptor expression and functional signaling in murine gonadotrope-like cells. J Endocrinol 200:223-32 |
