Добірка наукової літератури з теми "Pro-opiomelanocortin neurons"

Abstract Pro-opiomelanocortin (POMC) neurons in the hypothalamus play a role in both the control of metabolic state and sexual behavior. Along with the fast neurotransmitters glutamate and/or GABA, POMC neurons secrete cocaine- and amphetamine-regulated transcript (CART) and products of the POMC gene, including β-endorphin and α-melanocortin stimulating hormone (α-MSH). Published data from our lab demonstrate a lack of sexual interest in male mice when both the leptin receptor and insulin receptor are deleted from POMC neurons. Furthermore, this absence of interest correlates with a decrease in the POMC product α-MSH. However, it is not known whether these effects correspond to an increase in POMC neural activation. We hypothesized that activation of POMC neurons in male mice would lead to improved sexual interest. We have crossed mice with cre-dependent expression of the excitatory designer receptor, hM3Dq, with mice expressing cre under control of the POMC promoter. When these mice are administered intraperitoneal clozapine-N-oxide (CNO), POMC neurons exhibit increased activation. We completed a comprehensive mating analysis to measure the sexual desire and erectile and ejaculatory capabilities of these male mice under CNO or saline administration. Additionally, we sacrificed the mice after injection of CNO or saline to perform immunostaining for the protein c-fos as an indicator of neural activation. As expected, activation of POMC neurons with CNO increased c-fos expression, while the impact on male sexual interest was more nuanced. These experiments emphasize the need to investigate the specific neuropeptide and transmitter output by POMC neurons that influences sexual behavior and function.

✓ The distribution of pro-opiomelanocortin (β-endorphin, adrenocorticotropic hormone, and 16-K) neurons and fiber projections was evaluated immunocytochemically in 50-µ thick cryostat sections of human diencephalon and midbrain. Specific attention was focused upon regions in which deep brain stimulation has been most effective in the relief of selected chronic pain syndromes. This study revealed a remarkable, nearly point-to-point correlation between clinically effective stimulation sites and the distribution of pro-opiomelanocortin fibers in the human brain. Of particular interest was the dense innervation of the periventricular stratum along the third ventricle, the parafascicular centromedian region of the thalamus, and the periaqueductal gray matter of the midbrain. This study provides anatomical support for the hypothesis that β-endorphin-containing neuronal systems may contribute to stimulation analgesia in the human.

Melanocortin peptides, derived from POMC (pro-opiomelanocortin) are produced in the ARH (arcuate nucleus of the hypothalamus) neurons and the neurons in the commissural NTS (nucleus of the solitary tract) of the brainstem, in anterior and intermediate lobes of the pituitary, skin and a wide range of peripheral tissues, including reproductive organs. A hypothetical model for functional roles of melanocortin receptors in maintaining energy balance was proposed in 1997. Since this time, there has been an extraordinary amount of knowledge gained about POMC-derived peptides in relation to energy homoeostasis. Development of a Pomc-null mouse provided definitive proof that POMC-derived peptides are critical for the regulation of energy homoeostasis. The melanocortin system consists of endogenous agonists and antagonists, five melanocortin receptor subtypes and receptor accessory proteins. The melanocortin system, as is now known, is far more complex than most of us could have imagined in 1997, and, similarly, the importance of this system for regulating energy homoeostasis in the general human population is much greater than we would have predicted. Of the known factors that can cause human obesity, or protect against it, the melanocortin system is by far the most significant. The present review is a discussion of the current understanding of the roles and mechanism of action of POMC, melanocortin receptors and AgRP (agouti-related peptide) in obesity and Type 2 diabetes and how the central and/or peripheral melanocortin systems mediate nutrient, leptin, insulin, gut hormone and cytokine regulation of energy homoeostasis.

The mammalian CNS relies on a constant supply of external glucose for its undisturbed operation. However, neurons can readily switch to using fatty acids and ketones as alternative fuels. Here, we show that oleic acid (OA) excites pro-opiomelanocortin (POMC) neurons by inhibition of ATP-activated potassium (KATP) channels. The involvement of KATP channels is further supported by experiments in SUR1 KO animals. Inhibition of β-oxidation using carnitine palmitoyltransferase-1 inhibitors blocks OA-induced depolarization. The depolarizing effect of OA is specific because it is not mimicked by octanoic acid. Furthermore, OA does not regulate the excitability of agouti-related peptide neurons. High-fat feeding alters POMC neuron excitability, but not its response to OA. Thus β-oxidation in POMC neurons may mediate the appetite-suppressing (anorexigenic) effects of OA.

Les tanycytes du noyau arqué de l’hypothalamus (ARH) sont des cellules épendymogliales spécialisées se trouvant le long des parois du troisième ventricule (3V). Ils sont constitués d’un corps cellulaire polarisé dont la partie apicale entre en contact avec le liquide céphalo-rachidien (LCR) et dont la partie basale envoie un prolongement cytoplasmique vers les neurones du parenchyme nerveux. Leur localisation stratégique à l’interface entre le LCR contenant le glucose, et les neurones à pro-opiomélanocortine (POMC) répondant à des variations de glucose, renforce la possibilité que les tanycytes jouent un rôle important dans les mécanismes de détection hypothalamique du glucose, ainsi que dans le contrôle de la balance énergétique. Le but de ma thèse a été de tester l’hypothèse que les tanycytes de l’ARH formeraient un réseau métabolique de cellules interconnectées, au sein duquel le lactate, produit à partir du glucose circulant dans le LCR, diffuserait vers les neurones à POMC pour les alimenter en énergie, et les informer sur le statut glycémique de l’organisme afin de contrôler la balance énergétique. Les enregistrements électrophysiologiques ont indiqué qu’une majorité de neurones à POMC n’utilise pas le glucose, mais le lactate comme substrat énergétique pour soutenir leur activité électrique, via son métabolisme en pyruvate. Il a été montré que l’apport du lactate à ces neurones implique une navette fonctionnelle avec les tanycytes de l’ARH, dans laquelle ces derniers produisent le lactate à partir du glucose et le libèrent aux neurones à POMC via les transporteurs aux monocarboxylates (MCTs). De plus, les études ont démontré que la perturbation du réseau tanycytaire, formé par les connexines (Cxs) 43, conduit à une inhibition de l’activité électrique des neurones à POMC qui résulte d’un déficit de lactate dans l’ARH. De manière intéressante, il a été montré que le réseau tanycytaire contrôle la biodisponibilité du lactate dans cette région en réponse à des changements de taux circulants de glucose et régule le comportement alimentaire et le métabolisme énergétique chez les souris. Ces découvertes mettent en évidence un mécanisme utilisé par l’hypothalamus pour détecter les variations des taux circulants de glucose et pour maintenir la balance énergétique
Tanycytes of the arcuate nucleus of the hypothalamus (ARH) are specialized ependymoglial cells distributed along the lateral walls of the third ventricle (3V); their cell bodies contact the cerebrospinal fluid (CSF) while their processes arching in the tissue contact arcuate neurons. Their strategic location at the interface between the glucose-containing CSF and glucose-responsive proopiomelanocortin (POMC) neurons raises the possibility that tanycytes play a role in hypothalamic glucose detection mechanisms controlling energy balance. The aim of my thesis was to test the hypothesis that tanycytes convert glucose-containing CSF into lactate and distribute it to POMC neurons via a connexin 43 (Cx43)-mediated tanycytic metabolic networks, to control the energy balance. Electrophysiological recordings intriguingly indicated that most of the POMC neurons do not use glucose but lactate as energy substrate to sustain their electrical activity via its metabolism into pyruvate. The endogenous lactate required to sustain POMC neuronal activity is provided by ARH tanycytes via the conversion of glucose and shuttled to neurons via monocarboxylate transporters (MCTs). Furthermore, our study demonstrated that disruption of the Cx43-mediated tanycytic metabolic network leads to inhibition of POMC neuronal activity due to lactate deficiency into the ARH. These results thus show the importance of this network in the supply of lactate to POMC neurons. Finally, the tanycytic network was also shown to control the bioavailability of lactate in the ARH in response to changes in circulating glucose and to regulate feeding behavior and the energy metabolism in mice. Overall, our findings shed new lights on the mechanism used by the hypothalamus to monitor circulating levels of glucose and maintain of energy balance

Pro-opiomelanocortin (POMC) is a precursor polypeptide that can be differentially cleaved into various biologically active peptides that have diverse effects. POMC is produced in neurones that are located in two distinct regions of the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract in the medulla (NTS). POMC neurones in the ARC have been well described in terms of their anatomical distribution and functional role, however NTS POMC neurones have not. The NTS is a major structure involved in cardiorespiratory regulation and is also linked to nociceptive processing, where NTS stimulation is antinociceptive. ~-endorphin, a cleavage peptide of POMe, is an opioid known to produce potent and lasting analgesia and can also affect cardiorespiratory function. NTS POMC neurones could provide a source of ~endorphin release within the brainstem. This project will test the hypothesis that NTS POMC neurones are involved in cardiorespiratory and nociceptive processing, via release of ~-endorphin. This project has employed viral vector-mediated strategies in POMC-Cre-ROSAGFP mice in order to: (i) opto-activate NTS POMC-Cre neurones and examine effects on cardiorespiratory control in the working heart-brainstem preparation; (ii) study the anatomical projections of NTS POMC-Cre neurones throughout the brain; and (iii) pharmacologically activate NTS POMC-Cre neurones in awake, behaving mice to examine influence on respiratory function, food intake and nociception. Opto-activation of NTS POMC-Cre neurones elicited profound cardiorespiratory responses, including a bradycardia, transient apnoea and increased respiratory sinus arrhythmia. These responses were attenuated by systemic naloxone. The bradycardias were mimicked by DAMGO microinjection into the nucleus ambiguus (NA), but not NTS. NTS POMC-Cre neuronal fibres projected to specific target sites within the brainstem, including the NA, ventral respiratory column, dorsal motor nucleus of the vagus, raphe obscurus nucleus, lateral reticular nucleus and hypoglossal nucleus. Pharmaco-activation of NTS POMCCre neurones resulted in increased tail-flick latencies, which were abolished by systemic naloxone. Taken together these results show that activation of NTS POMC-Cre neurones can produce antinociceptive effects, exert a potent facilitatory influence on cardiac vagal outflow and can inhibit the respiratory network. These responses are likely to be mediated by the opioid peptide ~-endorphin. The projections of POMC-Cre neuronal fibres outside of the NTS suggest that they form an output path to other CNS sites. These results suggest that NTS POMC-Cre neurones may have an opioid-mediated role in autonomic modulation and somatic nociception.