ProTRH Gene Transcription and Biosynthesis by Leptin

Rhode Island Hospital, Providence RI

Investigators

Linked publications & trials

Abstract

Project Description Regulation of energy consumption is a pivotal mechanism for maintaining body weight. Hormones that regulate energy balance can be categorized into those that influence appetite and those that act to maintain body fat stores. The anorexigenic peptide leptin is released into the blood in proportion to the amount of body fat and plays a central role in activating the hypothalamic-pituitary-thyroid (HPT) axis, a key stimulator of energy expenditure. One very important energy expenditure regulator Thyrotropin Releasing Hormone (TRH) is produced in the paraventricular nucleus (PVN) of the hypothalamus. This neuropeptide regulates the output of thyroid hormone through the HPT axis. The function of the thyroid gland is to produce the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), which regulate transcription of numerous important genes through binding to a family of nuclear receptors in cells throughout the body. This gland provides an unchanging basal level of thyroid hormone to keep the basic metabolic rate of all cells at a constant level. Leptin resistance in diet-induced obese (DIO) rodents is typified by elevated serum leptin and a significantly decreased response to exogenous leptin. Leptin induces energy expenditure by acting on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been clearly reported. It has been suggested that this resistance is localized specifically at the level of the arcuate nucleus (ARC), but there is speculation concerning which specific nuclei within the ARC become leptin resistant. Beside the ARC there are other regions of the hypothalamus where leptin also acts through its ObRb receptor including the PVN and lateral hypothalamus. We have recently uncovered the existence of two subgroups of TRH neurons in the PVN responsive to leptin (direct, through phosphorylation of STAT3, and to [unreadable]-MSH (indirect, through phosphorylation CREB) (1), and since resistance to leptin is mostly located at the level of the ARC, we propose that the direct pathway of leptin action on TRH neurons remains sensitive. Therefore, in this competitive renewal, Aim #1. We will test the hypothesis that the HPT axis remains sensitive to leptin signaling in diet- induced obesity. Our understanding of the positive regulation of TRH production has been greatly advanced by previous work in this laboratory, however work must be done in determining the role of NPY (a strong inhibitor of TRH) in the negative regulation of TRH. Therefore: Aim #2. We will test the responsiveness of TRH neurons to NPY in lean versus DIO rats. Aim #3. We will test the hypothesis that NPY down regulates the prohormone convertases 1 and 2 (PC1/2). Aim #4. We will identify the role of the egr-1 transcription factor in regulating PC2 by leptin and NPY