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 ?-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
According to the World Health Organization, obesity in developed countries has reached epidemic proportions. There are globally more than 1 billion adults overweight, with around 300 million of them clinically obese. As consequence, the study of obesity has become a priority in the medical research. Still, the search for effective anti-obesity drugs has been unsuccessful. Initially, the discovery of the hormone leptin raised a lot of expectations, given its capacity to decrease appetite and body weight of obese leptin- deficient mice. However, it was soon established that most of obese humans and rodents have high levels of plasma leptin, which fail to reduce appetite and body weight. Many aspects of this leptin-resistant state are still unknown. A better understanding of leptin molecular mechanisms affecting neural circuits is essential to develop new strategies for the treatment of obesity. Leptin is a key regulator of the thyrotropin releasing hormone (TRH), a hormone produced in the brain and responsible for regulating the thyroid gland. The thyroid gland produces thyroid hormone, which is essential in thermogenesis, a mechanism to burn calories. Therefore, in this application we will investigate the mechanisms by which leptin, the melonocorting stimulating hormone (MSH) hormone, and the negative regulator peptide hormone NPY affects the TRH prohormone and the enzymes responsible for the maturation to TRH. The studies will be conducted in animals subjected to fed, fasting, and diet-induced obesity. The in vivo studies will be complemented with vitro approaches.
|Ramadori, Giorgio; Fujikawa, Teppei; Fukuda, Makoto et al. (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12:78-87|