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Montréal Trigonix inc. 2018

L’obésité se caractérise par un excès de masse adipeuse corporelle. Elle est due à un déséquilibre de la balance énergétique qui dépend de l’apport énergétique et les dépenses énergétiques, notamment via la thermogenèse du tissu adipeux brun (brown adipose tissue — BAT). Le BAT est sous l’influence de différents systèmes de neurotransmetteurs au sein du système nerveux central et en particulier au niveau de l’hypothalamus par le système mélanocortines (SM). Cependant, le rôle du SM dans l’hypothalamus sur le contrôle du BAT reste à éclaircir. Les travaux présentés dans cette thèse visaient à i) montrer que le noyau paraventriculaire de l’hypothalamus (PVH) est au centre de la modulation des effets du SM sur la thermogenèse du BAT par le système endocannabinoïde (SE) et ii) mettre en évidence que le noyau préoptique médial (MPO) est un site d’activation de la thermogenèse par les mélanocortines dépendant d’un relais dans le noyau dorsomédian de l’hypothalamus (DMH). Nous avons observé que l’injection intra-cérébro-ventriculaire de MTII, un agoniste des récepteurs aux mélanocortines, augmente la dépense énergétique via la thermogenèse du BAT. D’autre part, les effets du MTII sur le BAT sont inhibés ou partiellement potentialisés par l’injection respective d’un agoniste (Δ9-THC) ou d’un antagoniste (AM251) du SE. Par la suite, nous avons mis en évidence que ces observations font intervenir spécifiquement le récepteur aux mélanocortines 4 et le récepteur aux cannabinoïdes de type 1. Enfin, notre étude a montré que des neurones du PVH co-expriment ces deux récepteurs et que les effets sur la thermogenèse de l’injection de MTII dans le PVH, sont totalement inhibés par l’administration de Δ9-THC dans le 4éme ventricule, suggérant donc, que la modulation du SM par le SE a lieu au sein de neurones du PVH projetant vers la moëlle épinière. D’autre part, l’injection de MTII dans le MPO stimule la thermogenèse du BAT. Toutefois, des lésions du DMH causées par l’acide kaïnique inhibent les effets du MTII. De plus, l’expression de gènes impliqués dans le métabolisme du tissu adipeux blanc inguinal est stimulée par le MTII, mais seulement chez les rats lésés. Ces résultats permettent donc d’établir que le duo MPO-DMH est une cible importante dans la modulation de l’homéostasie énergétique par les mélanocortines. L’ensemble de ces résultats montre le rôle majeur du SM au sein de l’hypothalamus dans le contrôle de l’activité thermogène du BAT. Cependant, la compréhension des réseaux neuronaux impliquant le SM et ses co-régulateurs reste à éclaircir avant d’envisager un traitement thérapeutique de l’obésité via le SM. / Obesity is characterized by an adiposity excess. It is due to an imbalance between energy intake and energy expenditure, which includes a few components including brown adipose tissue (BAT) thermogenesis. BAT is controlled by different neuronal systems of the central nervous system, including the melanocortin system (MS). However, the role of the hypothalamic melanocortin system in the control of BAT thermogeneis remains unclear. The studies presented in this thesis were designed to study i) that the paraventricular nucleus of the hypothalamus (PVH) is central for modulating the effects of MS on BAT thermogenesis by the endocannabinoid system (ES) and ii) to highlight the influence of the medial preoptic nucleus (MPO) as a site of the thermogenic action of MS and exploring the role played by the dorsomedial nucleus of the hypothalamus (DMH) in this action. We observed that intracerebroventricular (i.c.v) injection of melanocotin II (MTII), a melanocortin receptor agonist, increased energy expenditure through BAT thermogenesis. The MTII effects on BAT were inhibited or partially potentiated by an injection of ES agonist (Δ9-THC) or antagonist (AM251) respectively. Subsequently, we demonstrated that the melanocortin 4 receptor and the cannabinoid receptor type 1 were specifically involved in these observations. Finally, our study showed that PVH neurons co-expressed both these receptors and the effects on thermogenesis of the MTII injection into the PVH were completely inhibited by the administration of Δ9-THC in the 4th ventricle, suggesting that the modulation of MS by the ES occurred through PVH neurons projecting to the spinal cord. On the other hand, the injection of MTII in MPO stimulated BAT thermogenesis. Nonetheless, DMH lesions caused by kainic acid inhibited the effects of MTII. Furthermore, the gene expression involved in inguinal white adipose tissue metabolism were stimulated by MTII, but only in lesioned rats. These results indicate that the MPO-DMH duet is an important target in the modulation of energy homeostasis by the melanocortins. All of these results show the major role of MS within the hypothalamus in the control of BAT thermogenic activity. However, understanding of neural networks involving the MS and its co-regulators remains to be clarified before considering therapeutic treatment of obesity through the activation of MS.

The present series of studies was undertaken to determine the effects of peripherally and centrally administered alpha-melanocyte stimulating hormone (MSH) on lordosis and to investigate some of the mechanisms underlying these effects. The results of Experiments 1-5 (Section I) indicated that, when confounding factors were minimized, peripherally administered MSH facilitated receptivity. Centrally administered MSH was found to produce both a long and a short term inhibitory effect. Experiment 6 (Section II) tested the hypothesis that the facilitatory action of peripherally administered MSH was due to an MSH-induced release of progesterone or some other facilitatory adrenal steroid. Results indicated that, while adrenalectomy per se did not inhibit lordosis, it blocked the facilitatory action of MSH, supporting the hypothesis. In Experiments 7-9 (Section III), the role of estrogen and progesterone in the inhibitory actions of MSH was examined. The results of these studies suggested that both estrogen and progesterone are necessary for the short term inhibitory action of MSH. However, the long term inhibitory action of MSH appears to be due, in part, to an MSH-induced decrease in the availability of cytoplasmic progestin receptors. In Experiments 10-15 (Section IV), the role of serotonin in the production of the inhibitory actions of MSH was examined. Parachlorophenyl-alanine (PCPA), a serotonin depletor, was found to prevent the long term inhbitory action of MSH. In addition, the inhibitory effects of PCPA or pirenperone, a serotonin type II receptor antagonist, did not summate with the inhibitory action of MSH. This suggested that serotonin type II receptors were involved in the production of the inhibitory actions of MSH. In Experiment 12, quipazine, a serotonin type II agonist, was found to attenuate fully the short term Inhibitory action of MSH. However, quipazine did not fully attenuate the long term inhibitory action of MSH, suggesting that the short and long term inhibitory actions of MSH are mediated through different mechanisms. This possibility was supported by the results of Experiment 13, which indicated that 20 ng MSH produced a long term, but not a short term, inhibitory effect. The results of Experiment 14 indicated that subthreshold doses of pirenperone and of MSH, when administered together, would inhibit receptivity. Experiment 15 indicated that this inhibition could be attenuated by quipazine. Thus, the following conclusions can be drawn: 1) the facilitatory action of peripherally administered MSH is probably mediated by an MSH-induced release of progesterone from the adrenals, 2) the short term inhibitory action of MSH is mediated, to a large extent, by an MSH-induced decrease in serotonin type II activity, and 3) the long term inhibitory action of MSH is mediated, in part, by an MSH/serotonin-induced decrease in the availability of progestin receptors. In addition, it was hypothesized that: 1) progesterone acts in the MRF to increase serotonin type II activity. Thus, MSH-induced decreases in serotonin type II activity and in progestin receptors probably occur at this location, and 2) estrogen acts in the AH-POA to decrease serotonin type I activity. Therefore, any actions of MSH on serotonin type I activity or on estrogen receptors is likely to occur in this region. Finally, it was suggested that MSH plays a role in the induction and maintenance of pseudopregnancy, thereby providing MSH with a functional role in the regulation of receptive states. / Arts, Faculty of / Psychology, Department of / Graduate

Thesis (M.S.)--Mississippi State University. Department of Biological Sciences. / Title from title screen. Includes bibliographical references.

Indiana University-Purdue University Indianapolis (IUPUI) / Immunotherapy for cancer has held much promise as a potent modality of cancer treatment. The ability to selectively destroy diseased cells and leave healthy cells unharmed has been the goal of cancer immunotherapy for the past thirty years. However, the full capabilities of cancer immunotherapies have been elusive. Cancer immunotherapies have been consistently hampered by limited immune reactivity, a diminishing immune response over time, and a failure to overcome self-tolerance. Many of these deficiencies have been borne-out by immunotherapies that have focused on the adoptive transfer of activated or genetically modified mature CD8+ T cells. The limitations inherent in therapies involving terminally differentiated mature lymphocytes include limited duration, lack of involvement of other components of the immune system, and limited clinical efficacy. We sought to overcome these limitations by altering and enhancing long-term host immunity by genetically modifying then transplanting HSCs. To study these questions and test the efficiency of gene transfer, we cloned a tumor reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen TRP-1, then constructed both a high expression lentiviral delivery system and a TCR Tg expressing the same TCR genes. We demonstrate with both mouse and human HSCs durable, high-efficiency TCR gene transfer, following long-term transplantation. We demonstrate the induction of spontaneous autoimmune vitiligo and a TCR-specific TH1 polarized memory effector CD4+ T cell population. Most importantly, we demonstrate the destruction of subcutaneous melanoma without the aid of vaccination, immune modulation, or cytokine administration. Overall, these results demonstrate the creation of a novel translational model of durable lentiviral gene transfer, the induction of spontaneous CD4+ T cell immunity, the breaking of self-tolerance, and the induction of anti-tumor immunity.