Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y.

Survival in a natural environment forces an individual into constantly adapting purposive behavior. Specified interoceptive neurons monitor metabolic and physiological balance and activate dedicated brain circuits to satisfy essential needs, such as hunger, thirst, thermoregulation, fear, or anxiety. Neuropeptides are multifaceted, central components within such life-sustaining programs. For instance, nutritional depletion results in a drop in glucose levels, release of hormones, and activation of hypothalamic and brainstem neurons. These neurons, in turn, release several neuropeptides that increase food-seeking behavior and promote food intake. Similarly, internal and external threats activate neuronal pathways of avoidance and defensive behavior. Interestingly, specific nuclei of the hypothalamus and extended amygdala are activated by both hunger and fear. Here, we introduce the relevant neuropeptides and describe their function in feeding and emotional-affective behaviors. We further highlight specific pathways and microcircuits, where neuropeptides may interact to identify prevailing homeostatic needs and direct respective compensatory behaviors. A specific focus will be on neuropeptide Y, since it is known for its pivotal role in metabolic and emotional pathways. We hypothesize that the orexigenic and anorexigenic properties of specific neuropeptides are related to their ability to inhibit fear and anxiety.

Control de la ingesta alimentaria: rol del receptor 4 de melanocortina en el desarrollo de obesidad / Role of melanocortin receptor 4 in the control of food intake and the development of obesity

Arquate nucleus, a convergence site of peripheral and central signals, plays a fundamental role in the control of food intake. Orexigenic neurons that secrete neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and anorexigenic neurons secreting Pro-opiomelanocortin (POMC) are involved in this action. Both groups of neurons respond to peripheral signals such as insulin and leptin and are reciprocally inhibited. alpha Type melanocyte stimulating hormone (alphaMSH), liberated by POMC neurons, reduces food intake activating melanocortin receptor 4 (MC4R), located in second order neurons of the paraventricular nucleus. NPY/AgRP antagonize the effects of this peptide on MC4R receptors,maintaining an inhibitory tone on áMHS liberation, mediated by the activation of gabaergic receptors of POMC neurons. The study of these mechanisms will allow the development of new medications, especially MC4R agonists, to reduce nutrient intake...

Melanocortin 1 receptor and skin pathophysiology: beyond colour, much more than meets the eye.

The melanocortin 1 receptor (MC1R), a G protein-coupled receptor preferentially expressed in melanocytes, mediates the pigmentary effects of α melanocyte-stimulating hormone (αMSH). MC1R is also expressed in other cutaneous cell types, particularly keratinocytes and dermal fibroblasts, suggesting non-pigmentary actions of the αMSH/MC1R system. Böhm and Stegemann now report a dramatic effect of mouse Mc1r functional status on susceptibility to skin fibrosis and collagen types I and III metabolism, in a study combining the powerful mouse model provided by the natural Mc1r(e/e) knockout and an established model of skin fibrosis. The study underscores the antifibrotic role for the skin αMSH/MC1R system.

Neuropeptides and central control of sexual behaviour from the past to the present: a review.

Of the numerous neuropeptides identified in the central nervous system, only a few are involved in the control of sexual behaviour. Among these, the most studied are oxytocin, adrenocorticotropin, α-melanocyte stimulating hormone and opioid peptides. While opioid peptides inhibit sexual performance, the others facilitate sexual behaviour in most of the species studied so far (rats, mice, monkeys and humans). However, evidence for a sexual role of gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin and galanin-like peptide, cholecystokinin, substance P, vasoactive intestinal peptide, vasopressin, angiotensin II, hypocretins/orexins and VGF-derived peptides are also available. Corticotropin releasing factor, neuropeptide Y, cholecystokinin, vasopressin and angiotensin II inhibit, while substance P, vasoactive intestinal peptide, hypocretins/orexins and some VGF-derived peptide facilitate sexual behaviour. Neuropeptides influence sexual behaviour by acting mainly in the hypothalamic nuclei (i.e., lateral hypothalamus, paraventricular nucleus, ventromedial nucleus, arcuate nucleus), in the medial preoptic area and in the spinal cord. However, it is often unclear whether neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except in a few cases (e.g., opioid peptides and oxytocin). Unfortunately, scarce information has been added in the last 15 years on the neural mechanisms by which neuropeptides influence sexual behaviour, most studied neuropeptides apart. This may be due to a decreased interest of researchers on neuropeptides and sexual behaviour or on sexual behaviour in general. Such a decrease may be related to the discovery of orally effective, locally acting type V phosphodiesterase inhibitors for the therapy of erectile dysfunction.

Mechanisms regulating melanogenesis.

Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances, has not yet been fully understood. The pigment melanin is produced in melanosomes by melanocytes in a complex process called melanogenesis. The melanocyte interacts with endocrine, immune, inflammatory and central nervous systems, and its activity is also regulated by extrinsic factors such as ultraviolet radiation and drugs. We have carried out a review of the current understanding of intrinsic and extrinsic factors regulating skin pigmentation, the melanogenesis stages and related gene defects. We focused on melanocyte-keratinocyte interaction, activation of melanocortin type 1 receptor (MC1-R) by peptides (melanocyte-stimulating hormone and adrenocorticotropic hormone) resulting from proopiomelanocortin (POMC) cleavage, and mechanisms of ultraviolet-induced skin pigmentation. The identification and comprehension of the melanogenesis mechanism facilitate the understanding of the pathogenesis of pigmentation disorders and the development of potential therapeutic options.

Mechanisms regulating melanogenesis* / Mecanismos reguladores da melanogênese

Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances, has not yet been fully understood. The pigment melanin is produced in melanosomes by melanocytes in a complex process called melanogenesis. The melanocyte interacts with endocrine, immune, inflammatory and central nervous systems, and its activity is also regulated by extrinsic factors such as ultraviolet radiation and drugs. We have carried out a review of the current understanding of intrinsic and extrinsic factors regulating skin pigmentation, the melanogenesis stages and related gene defects. We focused on melanocyte-keratinocyte interaction, activation of melanocortin type 1 receptor (MC1-R) by peptides (melanocyte-stimulating hormone and adrenocorticotropic hormone) resulting from proopiomelanocortin (POMC) cleavage, and mechanisms of ultraviolet-induced skin pigmentation. The identification and comprehension of the melanogenesis mechanism facilitate the understanding of the pathogenesis of pigmentation disorders and the development of potential therapeutic options.

A pigmentação da pele é um importante traço fenotípico do ser humano mas apesar dos recentes avanços a sua regulação não está ainda totalmente esclarecida. O pigmento melanina é produzido nos melanossomas pelos melanócitos, num processo complexo designado por melanogénese. O melanócito interatua com os sistemas endócrino, imunitário, inflamatório e nervoso central e a sua atividade é também regulada por fatores extrínsecos como a radiação ultravioleta e fármacos. Fizemos uma revisão do conhecimento atual sobre os fatores intrínsecos e extrínsecos reguladores da pigmentação cutânea, etapas da melanogénese e defeitos genéticos relacionados. Fizemos enfoque na interação melanócito-keratinócito, na ativação do receptor da melanocortina tipo 1 (MC1-R) pelos péptidos (hormona estimuladora do melanócito e hormona adrenocorticotrófica) resultantes da clivagem da proopiomelanocortina (POMC) e mecanismos da pigmentação induzida pela radiação ultravioleta. A identificação e compreensão dos mecanismos reguladores da pigmentação cutânea facilitam o conhecimento dos mecanismos patogénicos dos distúrbios da pigmentação e o desenvolvimento de potenciais opções terapêuticas.

[Genetic variations in energy balance regulation].

Single nucleotide polymorphism (SNP) near certain genes revealed association of FAT(fat mass and obesity-associated gene), MC4R (melanocortin 4 receptor gene), and other genes with obesity. Participation of the FAT expression products in the regulation of energy balance remains to be clarified. The function of MC4R encoding melanocortin 4 receptor (MC4R) is somewhat better understood. alpha-, beta-, and gamma-MSH encoded by the POMC gene bind to MC4R, reduce food intake, and slow down fat accumulation. Expression of POMC that codes MSH is enhanced by leptin binding to the receptor (LepRb) in hypothalamic neurons. Mutations in human and animal MC4R, POMC, and LEP genes are known to be associated with obesity. More than 60 mutations in MC4R, more than 20 mutations in POMC and fewer LEP mutations have been reported. Nonsense mutations and reading frame shifts block gene expression and thereby disrupt protein synthesis. Missense mutations frequently affect protein folding in endoplasmic reticulum; unfolded or misfolded proteins remain in the cytoplasm and undergo degradation. Certain missence mutations do not interfere with gene expression and folding of proteins but impair their functioning at the periphery. P.S127L mutation in MC4R, p.E206X and p.F144L mutations in POMC as well as other mutations in homozygous and heterozygous forms account for disturbed energy balance in man. The LEP gene has been reported to contain G133fsX15, p.R105X, p.R1O5W, and p.S141C mutations. As a rule, they are associated with obesity and other pathological conditions only in homozygous forms.

Immunosuppression and melanocyte proliferation.

Melanocytes are pigmented cells derived from the neural crest; their proliferation is restrained by immune system. The eruption of nevi after an immunosuppressive condition is a peculiar phenomenon indicating that the immune system may play a major role in limiting proliferation of melanocytes. In this review, we analyze the role of immunosuppressive regimens on melanocyte proliferation. In particular, we discuss the eruptive nevi phenomenon, which is determined by the inability of the immune system to inhibit melanocyte proliferation. These clinical observations indicate that the immune system has a pivotal role in restraining melanocyte proliferation. However, although the role of the immune system in the development of nonmelanoma skin cancer has been shown clearly in several studies involving organ transplant patients, the role of immunosuppression in melanoma genesis has not yet been established. Further investigations are required to establish the real immunogenicity of melanoma, particularly in the light of the dichotomy between the eruptive nevi phenomenon in immunosuppressed patients and the low incidence of melanoma in transplanted patients.

Possible paracrine function of alpha-melanocyte-stimulating hormone and inhibition of its melanin-dispersing activity by N-terminal acetylation in the skin of the barfin flounder, Verasper moseri.

Melanocyte-stimulating hormone (MSH) is generated from a precursor protein, proopiomelanocortin (POMC), mainly in the pituitary. The barfin flounder, Verasper moseri, expresses three different POMC genes (Pomc), among which Pomc-c is also expressed in the skin. Herein, we characterized the biological significance of POMC and MSH produced in barfin flounder skin. The reverse transcription polymerase chain reaction showed the expression of Pomc-c in isolated non-chromatophoric dermal cells. Mass spectrometry analyses of fractions of skin extract separated by high-performance liquid chromatography revealed the presence of a peptide with a molecular mass corresponding to Des-acetyl (Ac)-alpha-MSH-C derived from POMC-C. These results indicate that, in addition to endocrine functions, MSH in barfin flounder is associated with skin pigmentation via paracrine mechanisms. On the other hand, in vitro studies showed that Des-Ac-alpha-MSH-C dispersed pigments in both melanophores and xanthophores. These functions are similar to those of Des-Ac-alpha-MSH, which differs from Des-Ac-alpha-MSH-C only at the C-terminus, generated from POMC-A and -B. Alpha-MSH, which has an acetyl group at the N-terminus, led to pigment dispersion in xanthophores, but showed no effect in melanophores. A series of bioassays indicated that acetylation enhances MSH activity in xanthophores, but inhibits it in melanophores, suggesting that receptors for MSHs expressed in xanthophores and melanophores are different from each other.

Anatomy, function and regulation of neuropeptide EI (NEI).

This review is focused on the anatomy, role and behavior of neuropeptide-glutamic acid-isoleucine (NEI), providing a general report on the neuropeptide. In addition to hormone release, this peptide also takes part in the regulation of grooming behavior and locomotor activity. NEI is produced by cleavage of prepro-MCH that probably takes place at the Lys(129)-Arg(130) and Arg(145)-Arg(146) sites (the glycine residue on the C-terminus of NEI strongly suggests that this peptide is amidated). This same prohormone is also the precursor of MCH, widely studied in relation to food and water intake, and NGE, of which little is known. NEI and MCH are extensively colocalized throughout the central nervous system (CNS), and NEI is also present in peripheral tissues. The latter is also effective in stimulating luteinizing hormone (LH) release and, to a lesser extent, FSH from primary pituitary cell cultures. In addition to releasing LH from the medial eminence, NEI also acts directly on gonadotropes. Lastly, this neuropeptide also acts at the CNS level on gonadotropin-releasing hormone (GnRH) neurons.

New targets for obesity pharmacotherapy.

An understanding of the mechanisms that regulate energy homeostasis is essential for understanding novel obesity therapies. The status of energy reserves is communicated to the brain by adiposity and satiety signals. These signals modify either anabolic or catabolic pathways and, consequently, alter food intake in line with signaled energy requirements. New antiobesity therapies are in development that target anabolic or catabolic regulatory networks to reduce food intake and/or increase energy expenditure to promote weight loss.

Cardiovascular and renal actions of melanocyte-stimulating hormone peptides.

PURPOSE OF REVIEW: Melanocyte stimulating hormones (MSHs, melanocortins) have important roles in feeding and energy metabolism and in inflammation. Recent observations have uncovered major functions for these peptides, particularly gamma-MSH, in cardiovascular regulation and sodium metabolism. RECENT FINDINGS: Both alpha- and gamma-MSH acutely elevate blood pressure and heart rate through central stimulation of sympathetic nervous outflow. This action of alpha-MSH is mediated by the melanocortin 4 receptor (MC4R), whereas sympathetic nervous stimulation by gamma-MSH does not involve its receptor MC3R but rather is likely due to activation of a sodium channel in the central nervous system. In contrast, gamma-MSH deficiency in rodents, or disruption of MC3R, leads to marked salt-sensitive hypertension, again through a central mechanism: a small dose of exogenous peptide delivered into the cerebroventricular system of mice with gamma-MSH deficiency restores blood pressure to normal. This salt-sensitive hypertension is accompanied by the development of insulin resistance; the mechanism linking these two consequences of a high-salt diet is not yet known but may involve activation of the sympathetic nervous system. SUMMARY: The study of MSH peptides in blood pressure regulation offers a new opportunity to gain insight into the mechanisms underlying salt sensitivity and its link to insulin resistance, and to new therapies.

Overview of endogenous and synthetic melanocortin peptides.

The melanocortin system consists of five seven-transmembrane spanning G-protein coupled (GPCRs) receptors (MC1R-MC5R), the endogenous agonists a-, B- and melanocyte stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), and the endogenous antagonists Agouti and Agouti-related protein (AGRP). Melanocortin agonists are involved in the regulation of feeding behavior and weight omeostasis in mammals. Structure-activity relationships (SAR) have been performed on the endogenous melanocortin receptor agonists and antagonists that have identified ligand amino acid residues implicated as important for receptor binding and stimulation. Knowledge of putative ligand-receptor interactions may help to design molecules as therapeutic agents for the treatment of physiological diseases.

The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models.

A little more than a decade ago, the molecular basis of the lipostat was largely unknown. At that time, many laboratories were at work attempting to clone the genes encoding the obesity, diabetes, fatty, tubby and agouti loci, with the hope that identification of these obesity genes would help shed light on the process of energy homeostasis, appetite and energy expenditure. Characterization of obesity and diabetes elucidated the nature of the adipostatic hormone leptin and its receptor, respectively, while cloning of the agouti gene eventually led to the identification and characterization of one of the key neural systems upon which leptin acts to regulate intake and expenditure. In this review, we describe the neural circuitry known as the central melanocortin system and discuss the current understanding of its role in feeding and other processes involved in energy homeostasis.

Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers.

Clear cell sarcoma (CCS) harbors a pathognomonic chromosomal translocation fusing the Ewing's sarcoma gene (EWS) to the CREB family transcription factor ATF1 and exhibits melanocytic features. We show that EWS-ATF1 occupies the MITF promoter, mimicking melanocyte-stimulating hormone (MSH) signaling to induce expression of MITF, the melanocytic master transcription factor and an amplified oncogene in melanoma. Knockdown/rescue studies revealed that MITF mediates the requirement of EWS-ATF1 for CCS survival in vitro and in vivo as well as for melanocytic differentiation. Moreover, MITF and TFE3 reciprocally rescue one another in lines derived from CCS or pediatric renal carcinoma. Seemingly unrelated tumors thus employ distinct strategies to oncogenically dysregulate the MiT family, collectively broadening the definition of MiT-associated human cancers.

Regulation of pigmentation in zebrafish melanophores.

In comparison with the molecular genetics of melanogenesis in mammals, the regulation of pigmentation in poikilothermic vertebrates is poorly understood. Mammals undergo morphological colour change under hormonal control, but strikingly, many lower vertebrates display a rapid physiological colour change in response to the same hormones. The recent provision of extensive genome sequencing data from teleost zebrafish, Danio rerio, provides the opportunity to define the genes and proteins mediating this physiological pigment response and characterise their function biologically. Here, we illustrate the background adaptation process in adults and larvae and describe a novel assay to visualize and directly quantify the rate of zebrafish melanophore pigment translocation in unprecedented detail. We demonstrate the resolution of this assay system; quantifying the zebrafish melanophore response to melanin-concentrating and melanocyte-stimulating hormones. Furthermore, we investigate the intracellular signalling downstream of hormone stimulation and the biomechanical processes involved in zebrafish pigment translocation, confirming the importance of cyclic adenosine monophosphate (cAMP) as a mediator of pigment translocation and finding intact microtubules are essential for both melanin dispersion and aggregation in zebrafish, but that microfilament disruption affects aggregation only. In conclusion, we propose these data establish the zebrafish as an experimental model for studying both physiological colour change and the molecular basis of pigment translocation.

To eat or not to eat; regulation by the melanocortin system.

The central melanocortin (MC) system is one of the best-characterized neuropeptidergic systems involved in the regulation of energy balance. This short review describes the role of the central MC system in feeding behavior. Pharmacological, anatomical and genetic studies show that activation of the MC system reduces meal size, whereas de-activation of the MC system increases meal size. Several brain regions, including distinct hypothalamic nuclei and the hindbrain, are involved in this process. Further dissection of MC pathways in feeding behavior is the subject of recent and probably future studies. As the MC system is involved in animal models of obesity and (possibly) anorexia, it appears that this is a target system for development of drugs for the treatment of disturbed human eating behavior.

Molecular biology and physiology of the melanocortin system in fish: a review.

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene (in particular adrenocorticotropic hormone, ACTH, and melanocyte-stimulating hormones, MSH) and five melanocortin receptor subtypes (MC1R-MC5R). Knowledge of the melanocortin system in fish is still limited, but information on the receptor part of the system is very rapidly growing. The melanocortin receptors (MCRs) have been recently cloned from several species of fish. The amino acid sequences appear remarkably well conserved. Pharmacological characterisation studies of the first identified piscine MCRs indicate that ACTH may be the original ligand for the MCRs, while the MSH peptides gained specialised functions in the course of evolution. Considering the tissue distribution of the MCRs, there are two distinctions between mammals and fish: where in mammals the MC4R is exclusively expressed in the central nervous system, in the fish species examined so far it is also peripherally expressed. It does however, alike the situation in mammals, likely play a key role in the central regulation of food intake and energy balance. Not only the MCRs, but also many other factors involved herewith, have been found in fish and roughly appear to function similarly as in mammals. The second difference is the distribution of the MC5R, which appears less widely expressed in fish than in mammals. Considering the available data it is predicted that, in mammals and fish alike, skin colouration is mediated via MC1R and steroidogenesis via MC2R. This review provides a short overview of the basic molecular characteristics, pharmacology, and tissue distribution of the MCRs in the fish investigated up to now, as well as their physiological role in the processes of skin colouration, steroidogenesis, and feeding behaviour.

Leptin and inflammation-associated cachexia in chronic kidney disease.

Leptin is an adipocyte-derived hormone that acts as a major regulator of food intake and energy homeostasis. It circulates both as a free and as a protein-bound entity. Leptin is released into the blood in proportion to the amount of body fat and exerts sustained inhibitory effects on food intake while increasing energy expenditure. The leptin receptor belongs to the class I cytokine receptor superfamily and possesses strong homology to the signal-transducing subunits of the IL-6 receptor. The hypothalamic melanocortin system, and specifically the melanocortin-4 receptor (MC-4R), is critical in mediating leptin's effect on appetite and metabolism. Serum leptin concentrations are elevated in patients with chronic kidney disease (CKD) and correlate with C-reactive protein levels suggesting that inflammation is an important factor that contributes to hyperleptinemia in CKD. Hyperleptinemia may be important in the pathogenesis of inflammation-associated cachexia in CKD. We showed that experimental uremic cachexia was attenuated in db/db mice, a model of leptin receptor deficiency. Nephrectomy in these animals did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption. Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R. MC-4R knockout mice or mice administered the MC-4R and MC-3R antagonist, agouti-related peptide, resisted uremia-induced loss of lean body mass and maintained normal basal metabolic rates. Thus, melanocortin receptor antagonism may provide a novel therapeutic strategy for inflammation-associated cachexia in CKD.