This study will be performed in Hungary in collaboration with Dr. Ronald M. Lechan as an extension of NIH grant #RO1 DK-37021 (06/01/2003-04/30/2008) to elucidate the importance of a new and novel substance with potent anorexic actions, oleylethanolamine (OEA), in the regulation of the hypothalamic-pituitary-thyroid axis during fasting. Since we observed in our preliminary studies that OEA inhibits the fasting-induced activation of cfos in NPY neurons in the arcuate nucleus, and NPY exerts a potent, inhibitory effect on the hypothalamic- pituitary-thyroid (HPT) axis, we propose that OEA contributes to the central regulation of thyroid function and will increase TRH gene expression in a discrete population of TRH neurons in the hypothalamic paraventricular nucleus (PVN) that are involved in regulation of the HPT axis. We will first explore the effect of acute and chronic OEA administration to fasted rats on the gene expression of feeding-related peptides in the hypothalamic arcuate nucleus and on thyrotropin-releasing hormone (TRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) using semiquantitative in situ hybridization. As existing data indicate that the anorexic effects of OEA are mediated through the brainstem, we will determine whether any regulatory effects of OEA on the arcuate nucleus and/or TRH neurons in the PVN are altered by a unilateral knife cut that will disconnect ascending brainstem fibers from the hypothalamus. Finally, we will determine whether OEA- induced effects on the HPT axis and the anorexic actions of OEA are mediated exclusively through NPY/AGRP-synthesizing neurons in the arcuate nucleus using a transgenic mouse model in which arcuate nucleus NPY/AGRP neurons can be selectively ablated in adult animals by a single intraperitonial dose of diphteria toxin. These studies will provide important information about the effects of OEA on the HPT axis and elucidate the central pathways mediating the anorexic effects of OEA. Given that OEA has the potential for being developed into a promising, orally active anti-obesity drug, we propose that the successful outcome of these studies will provide important insights about the central pathways underlying the effects of this molecule on the energy metabolism.
Obesity is an increasingly prevalent condition in both the United States and Hungary, associated with diabetes, high blood pressure, coronary disease and cancer. There are few effective anti-obesity treatments. Oleylethanolamide (OEA) is a recently described anorexigenic agent that has been shown to effectively reduce body weight after oral administration. Accordingly, OEA may be an attractive candidate for the treatment of obesity. In addition to furthering our knowledge about the factors that influence the HPT axis, therefore, understanding the central mechanisms by which OEA effects energy expenditure would be essential first steps before embarking upon a drug development program that could be applied to man.
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