RESUMO
Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.
Assuntos
Craniofaringioma , Doenças Hipotalâmicas , Neoplasias Hipofisárias , Humanos , Leptina/metabolismo , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/terapia , Doenças Hipotalâmicas/metabolismo , Obesidade/complicações , Obesidade/terapia , Obesidade/genética , Hipotálamo/metabolismo , Craniofaringioma/complicações , Craniofaringioma/terapia , Craniofaringioma/metabolismo , Hiperfagia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Melanocortinas/metabolismo , Metabolismo Energético/fisiologiaRESUMO
Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.
Assuntos
Melanocortinas , alfa-MSH , Humanos , Melanocortinas/metabolismo , Receptores de Melanocortina/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , InflamaçãoRESUMO
Melanocortins are tiny protein molecules formed by the post-translational cleavage of proopiomelanocortin. These are bioactive peptides that are responsible for human and lower animal pigmentation patterns, energy homeostasis, and sexual function modulation. These peptides regulate numerous physiological functions by being generated in the central nervous system and peripheral tissues. Melanocortins elicit their varied biological effects by binding to a separate family of G protein, two primary proteolytic enzymes, proconvertases 1 and 2, according to recent research. These breakthroughs have opened up new avenues for research into the role of melanocortins, antagonists, and receptors in a number of physiological activities.
Assuntos
Receptores de Melanocortina , Animais , Humanos , Inflamação/metabolismo , Melanocortinas/metabolismo , Peptídeos , Pigmentação , Receptores de Melanocortina/fisiologia , Estresse Psicológico/metabolismo , Disfunções Sexuais Fisiológicas/metabolismo , Masculino , Feminino , Alterações do Peso CorporalRESUMO
BACKGROUND: The melanocortin receptor accessory proteins (MRAP1 and MRAP2) are well-known endocrine regulators for the trafficking and signalling of all five melanocortin receptors (MC1R-MC5R). The observation of MRAP2 on regulating several non-melanocortin G protein-coupled receptors (GPCRs) has been sporadically reported, whereas other endogenous GPCR partners of the MRAP protein family are largely unknown. METHODS: Here, we performed single-cell transcriptome analysis and drew a fine GPCR blueprint and MRAPs-associated network of two major endocrine organs, the hypothalamus and adrenal gland at single-cell resolution. We also integrated multiple bulk RNA-seq profiles and single-cell datasets of human and mouse tissues, and narrowed down a list of 48 GPCRs with strong endogenous co-expression correlation with MRAPs. RESULTS: 36 and 46 metabolic-related GPCRs were consequently identified as novel interacting partners of MRAP1 or MRAP2, respectively. MRAPs exhibited protein-protein interactions and varying pharmacological properties on the surface translocation, constitutive activities and ligand-stimulated downstream signalling of these GPCRs. Knockdown of MRAP2 expression by hypothalamic administration of adeno-associated virus (AAV) packed shRNA stimulated body weight gain in mouse model. Co-injection of corticotropinreleasing factor (CRF), the agonist of corticotropin releasing hormone receptor 1 (CRHR1), suppressed feeding behaviour in a MRAP2-dependent manner. CONCLUSIONS: Collectively, our study has comprehensively elucidated the complex GPCR networks in two major endocrine organs and redefined the MRAP protein family as broad-spectrum GPCR modulators. MRAP proteins not only serve as a vital endocrine pivot on the regulation of global GPCR activities in vivo that could explain the composite physiological phenotypes of the MRAP2 null murine model but also provide us with new insights of the phenotyping investigation of GPCR-MRAP functional complexes.
Assuntos
Proteínas de Transporte , Receptores de Melanocortina , Animais , Humanos , Camundongos , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Melanocortinas/metabolismo , Glândulas Suprarrenais/metabolismo , Hipotálamo/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, ß-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs).
Assuntos
Hormônios Estimuladores de Melanócitos , beta-Defensinas , Hormônios Estimuladores de Melanócitos/metabolismo , Ligantes , Lipocalina-2 , Hormônio Adrenocorticotrópico/metabolismo , beta-Defensinas/metabolismo , Receptores de Melanocortina/química , Receptores de Melanocortina/metabolismo , Melanocortinas/metabolismoRESUMO
The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.
Assuntos
Melanocortinas , Pró-Opiomelanocortina , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Humanos , Hipotálamo/metabolismo , Melanocortinas/metabolismo , Obesidade/metabolismo , Peptídeos/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismoRESUMO
Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes1,2, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17ß-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3-7 projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity8 - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women9. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.
Assuntos
Encéfalo/fisiologia , Estrogênios/metabolismo , Esforço Físico/fisiologia , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais , Animais , Sistemas CRISPR-Cas , Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Estrogênios/deficiência , Feminino , Edição de Genes , Hipocampo/metabolismo , Masculino , Melanocortinas/metabolismo , Camundongos , Neurônios/metabolismo , Obesidade/metabolismo , Rombencéfalo/metabolismo , Comportamento Sedentário , Caracteres Sexuais , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
Neuropeptide AF (NPAF) decreases food and water intake in birds and food intake in mammals. In this study, the objective was to determine the effects of centrally administered NPAF on food and water intake, hypothalamic c-Fos immunoreactivity and hypothalamic mRNA abundance of appetite-regulating factors in Japanese quail (Coturnix japonica). Seven days post hatch, 6 h fasted quail were intracerebroventricularly (ICV) injected with 0 (vehicle), 4, 8, or 16 nmol of NPAF and food and water intake were measured at 30 min intervals for 180 min. In Experiment 1, chicks which received 4, 8, and 16 nmol ICV NPAF had reduced food intake for 120, 60 and 180 min following injection, respectively, and reduced water intake during the entire 180 min observation. In Experiment 2, there was increased c-Fos immunoreactivity in the paraventricular nucleus, the ventromedial nucleus of the hypothalamus, and the dorsomedial hypothalamic nucleus in NPAF-injected quail. In Experiment 3, ICV NPAF was associated with decreased corticotropin-releasing factor mRNA, and an increase in hypothalamic proopiomelanocortin and melanocortin receptor 4 mRNA. These results demonstrate that central NPAF suppresses food and water intake in quail, effects that are likely mediated via the melanocortin system in the hypothalamus.
Assuntos
Apetite/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Melanocortinas/metabolismo , Oligopeptídeos/administração & dosagem , Animais , Anorexia/induzido quimicamente , Hormônio Liberador da Corticotropina/metabolismo , Coturnix/metabolismo , Modelos Animais de Doenças , Hipotálamo/metabolismo , Infusões Intraventriculares , Núcleo Hipotalâmico Paraventricular , Pró-Opiomelanocortina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
The arcuate nucleus (ARC) of the hypothalamus comprises two antagonistic neuron populations critical for energy balance, namely, the anorexigenic pro-opiomelanocortin (POMC) and the orexigenic agouti-related peptide (AgRP) neurons that act as agonists and antagonists, respectively, for neurons expressing the type IV melanocortin receptor (MC4R) (Andermann ML and Lowell BB. Neuron 95: 757-778, 2017). MC4R activation increases energy expenditure and decreases food intake during positive energy balance states to prevent diet-induced obesity (DIO). Work from our group identified aberrant neuronal cell cycle events both as a novel biomarker and druggable target in the ARC for the treatment of DIO, demonstrating pharmacological restoration of retinoblastoma protein function in the ARC using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors could treat DIO in mice by increasing lipid oxidation to selectively decrease fat mass. However, the role of CDK4/6 inhibitors on food intake was not examined. Four-week-old Mc4r-loxTB mice were continuously administered high-fat diet (60% kcal fat). At 8 wk of age, animals were administered 60 mg/kg abemaciclib orally or a saline control and monitored every 2 wk for fat mass changes by MRI. At 11 wk of age, all animals were injected bilaterally in the paraventricular hypothalamus with AAV8 serotype virus expressing a Cre-mCherry and monitored for another 5 wk. Restoration of Mc4r expression in the paraventricular hypothalamic nucleus (PVN/PVH) reduced food intake in hyperphagic obese mice when given CDK4/6 inhibitor therapy. The reduced food intake was responsible for reduced fat mass in mice treated with abemaciclib. These results indicate that targeting POMC neurons could be an effective strategy in treating diet-related obesity.NEW & NOTEWORTHY We have defined some of the necessary components to prevent high-fat diet-induced obesity at the molecular and cellular level. Within POMC neurons, the retinoblastoma protein must remain active and prevented from phosphoinactivation by cyclin-dependent kinases. The downstream neurons within the PVH must also properly express MC4R for the circuit to appropriately regulate feeding behavior.
Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Melanocortinas/metabolismo , Rede Nervosa/efeitos dos fármacos , Obesidade/tratamento farmacológico , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.
Assuntos
Antineoplásicos/efeitos adversos , Caquexia , Citocinas , Comportamento de Doença , Inflamação , Melanocortinas/metabolismo , Atividade Motora , Paclitaxel/efeitos adversos , Condicionamento Físico Animal/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Caquexia/induzido quimicamente , Caquexia/metabolismo , Caquexia/terapia , Citocinas/sangue , Citocinas/efeitos dos fármacos , Fadiga/induzido quimicamente , Fadiga/metabolismo , Fadiga/terapia , Feminino , Febre/induzido quimicamente , Febre/metabolismo , Febre/terapia , Grelina/sangue , Grelina/efeitos dos fármacos , Comportamento de Doença/efeitos dos fármacos , Comportamento de Doença/fisiologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/terapia , Leptina/sangue , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Melanocortins are neuropeptides exerting versatile functions in the nervous system. Melanocortin 4 receptor (MC4R) is primarily expressed in the brain and is thought to be a major mediator for melanocortin. Brain-derived neurotrophic factor (BDNF) may be a crucial downstream molecule of MC4R activation, to yield neurite outgrowth, neuroregenerative, anorexigenic and other actions. In this study, we stimulated Neuro2a murine neuronal cells with an α-melanocyte stimulating hormone (α-MSH) analog, [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH). In Neuro2a cells, NDP-MSH promoted neurite outgrowth. Upon NDP-MSH administration, BDNF expression was greatly enhanced. Furthermore, this effect was effectively reversed by the MC4R antagonist, JKC-363. We found that NDP-MSH treatment activated the ERK cascade and its downstream kinase MSK1 (mitogen- and stress-activated protein kinase-1). Antagonism of the MSK1 cascade by a specific inhibitor or overexpression of a defective MSK1 mutant interrupted the phosphorylation of the transcription factor cAMP-response element binding protein (CREB), blocking BDNF upregulation. In addition, MSK1 activation triggered an epigenetic alteration in histone H3 (Ser10), facilitating the expression of the BDNF gene. Taken together, our results showed that MSK1 kinase positively activates MC4R-induced BDNF expression via modulating the phosphorylation of CREB and histone H3 in Neuro2a neuronal cells.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Melanocortinas/metabolismo , Neurônios/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Camundongos , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismoRESUMO
Melanocortin-2 receptor accessory protein (MRAP) has an unusual dual topology and influences the expression, localisation, signalling and internalisation of the melanocortin receptor 2 (MC2); the adrenocorticotropic hormone (ACTH) receptor. Mutations in MRAP are associated with familial glucocorticoid deficiency type-2 and evidence is emerging of the importance of MRAP in adrenal development and ACTH signalling. Human MRAP has two functional splice variants: MRAP-α and MRAP-ß, unlike MRAP-ß, MRAP-α has little expression in brain but is highly expressed in ovary. MRAP2, identified through whole human genome sequence analysis, has approximately 40% sequence homology to MRAP. MRAP2 facilitates MC2 localisation to the cell surface but not ACTH signalling. MRAP and MRAP2 have been found to regulate the surface expression and signalling of all melanocortin receptors (MC1-5). Additionally, MRAP2 moderates the signalling of the G-protein coupled receptors (GCPRs): orexin, prokineticin and GHSR1a; the ghrelin receptor. Whilst MRAP appears to be mainly involved in glucocorticoid synthesis, an important role is emerging for MRAP2 in regulating appetite and energy homeostasis. Transgenic models indicate the importance of MRAP in adrenal gland formation. Like MC3R and MC4R knockout mice, MRAP2 knockout mice have an obese phenotype. In vitro studies indicate that MRAP2 enhances the MC3 and MC4 response to the agonist αMSH, which, like ACTH, is produced through precursor polypeptide proopiomelanocortin (POMC) cleavage. Analysis of cohorts of individuals with obesity have revealed several MRAP2 genetic variants with loss of function mutations which are causative of monogenic hyperphagic obesity with hyperglycaemia and hypertension. MRAP2 may also be associated with female infertility. This review summarises current knowledge of MRAP and MRAP2, their influence on GPCR signalling, and focusses on pathophysiology, particularly familial glucocorticoid deficiency type-2 and obesity.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Insuficiência Adrenal/genética , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo de Esteroides/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Insuficiência Adrenal/metabolismo , Animais , Regulação do Apetite , Humanos , Insulina/metabolismo , Melanocortinas/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/metabolismoRESUMO
The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and ß-arrestin2 recruitment, using the two endogenous agonists, α- and ß-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.
Assuntos
Mutação , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Leptina/metabolismo , Ligantes , Melanocortinas/metabolismo , Modelos Teóricos , Obesidade/genética , Fosforilação , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/metabolismo , alfa-MSH/metabolismoRESUMO
In recent years, the effectiveness of high-dose metformin (MF) to treat the endocrine and oncological diseases has been shown. However, the use of high-dose MF may be associated with the lactic acidosis and the liver dysfunctions. The aim of the work was to study the effect of long-term (10 days) oral administration of a relatively high dose of MF (600 mg/kg per day) into yellow C57Bl/6J (Ay/a) Agouti line mice with the melanocortin type obesity on the liver function, which was evaluated by the morphology of hepatocytes and the severity of steatosis, the expression of the inflammatory and apoptotic factors of and the activity of aminotransferases, as well as on the plasma lactate level in the animals. In Agouti line mice, MF (600 mg/kg per day) caused a decrease in the body and fat weight, led to the reduced hyperglycemia, hyperinsulinemia and hyperleptinemia, and restored the sensitivity to glucose and insulin. At the same time, in the liver of Agouti line mice treated with MF, the small-drop and large-drop fatty degeneration and the hydropic degeneration were attenuated, and the expression of pro-inflammatory IL-1ß and pro-apoptotic Bax protein and the Bax/Bcl-2 ratio did not differ from the control C57Bl/6J (a/a) mice. In the blood of Agouti line mice treated with MF, the activity of alanine aminotransferase was normalized, and the lactate levels was increased, but to a moderate degree. It was concluded that the high-dose MF did not induce the lactic acidosis in Agouti line mice, and at the same time it restored the liver functions impaired in the melanocortin obesity. This allows us to consider the use of the high doses of MF as one of the possible ways to treat obesity and metabolic disorders that are associated with the hepatic steatosis.
Assuntos
Fígado , Melanocortinas , Metformina , Obesidade , Animais , Camundongos , Fígado/efeitos dos fármacos , Melanocortinas/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/fisiopatologiaRESUMO
Appetite and reproduction are closely related functions that are both regulated by brain hormones. Appetite stimulators include orexin and neuropeptide Y (NPY), and reproductive hormones include gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin, and neurokinin B (NKB). GnRH stimulates the secretion of pituitary gonadotropes, and kisspeptin and GnIH modulate this action. Kisspeptin secretion is further controlled by neurokinin B (NKB) and dynorphin A (Dyn). To better understand the mechanisms regulating appetite and reproduction in fish, we examined the effects of fasting, reproductive stage, gender, and strain on the brain mRNA expression of appetite (orexin and NPY) and reproductive (GnRH, kisspeptin, GnIH, and NKB) hormones in zebrafish. In order to compare strains, we used both wild-type and transparent Casper zebrafish. In female wild-type zebrafish, fasting increased the expression of all hormones investigated, with the exception of Kiss2. Only NPY and Kiss2 were increased in male wild-type zebrafish during fasting. In Casper zebrafish, only GnIH and NKB in males were affected by fasting, suggesting that Casper fish may be more resistant to fasting than wild fish. Fasting increased expressions of orexin, GnRH2, Kiss1, GnIH and NKB in wild-type females with more eggs or larger eggs relative to body weight, compared to those with fewer or smaller eggs, suggesting that more mature females are more affected by fasting. No significant interactions of fasting and reproductive stage were noted in female Casper fish. To investigate whether differences between Casper and wild-type fish were due to genes involved in pigmentation, we compared the brain mRNA expressions of enzymes involved in melanin synthesis (tyrosinase and tyrosine hydroxylase - TH), melanocortin receptors (MC3R and MC4R), and the melanocortin precursor (proopiomelanocortin - POMC) between the two strains. Casper zebrafish had lower levels of MC3R, tyrosinase, TH1, TH2, and POMC than wild-type fish. Overall, our results suggest the existence of gender- and reproductive stage-specific, as well as strain-specific variations in the mechanisms regulating feeding and reproduction in zebrafish, and that the melanocortin system and melanin pathways may be in part responsible for these differences between strains.
Assuntos
Apetite/genética , Jejum/metabolismo , Regulação da Expressão Gênica , Hormônios/metabolismo , Mutação/genética , Reprodução/fisiologia , Peixe-Zebra/genética , Animais , Encéfalo/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Masculino , Melaninas/biossíntese , Melanocortinas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade da Espécie , Peixe-Zebra/metabolismoRESUMO
Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.
Assuntos
Adiposidade/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Neurotensina/farmacologia , Obesidade/metabolismo , Animais , Glicemia/metabolismo , Preparações de Ação Retardada , Sinergismo Farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Melanocortinas/metabolismo , Camundongos , Camundongos Knockout , PolietilenoglicóisRESUMO
The initial discovery that ob/ob mice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the 'starved state' activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.
Assuntos
Apetite/fisiologia , Melanocortinas/metabolismo , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Transdução de Sinais/fisiologia , Animais , Fármacos Antiobesidade/farmacologia , Humanos , Camundongos , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Núcleo Hipotalâmico Paraventricular/metabolismo , Peptídeos/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/metabolismoRESUMO
Excessive alcohol intake induces an inflammatory response in the brain, via TNFα, TLR4 and NF-κB signaling pathways. It has been proposed that neuroinflammation would play a very important role in the development of alcohol addiction. In addition to stimulating the synthesis of inflammatory mediators such as IL-6, IL-1ß and TNFα, NF-κB is capable of reducing the anti-inflammatory activity of PPARα and PPARγ. Reciprocally, PPARα, PPARγ and melanocortin 4 receptor (MC4R) can decrease the proinflammatory activity of NF-κB, establishing an interplay of inactivations between such nuclear factors and receptors. In this review, we hypothesize that one of the mechanisms by which alcohol produces neuroinflammation is through NF-κB-mediated decrease in PPARα and PPARγ anti-inflammatory activities; in addition, ethanol negatively affects MC4R activity, decreasing the ability of this receptor to activate PPARγ. PPARα, PPARγ and MC4R can be pharmacologically activated by synthetic ligands (fibrates, thiazolidinediones and synthetic peptides, respectively); in this context, we propose that the administration of such ligands would decrease neuroinflammation produced by alcohol intake. The advantage of this approach is that fibrates and thiazolidinediones are FDA-approved drugs that have been used for years in other clinical conditions, and now may offer a new perspective for the treatment of alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Inflamação/etiologia , Melanocortinas/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Receptores Toll-Like/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Etanol/efeitos adversos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , LigantesRESUMO
Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Melanocortinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Termogênese/fisiologia , Animais , Biomarcadores , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação a DNA/genética , Orelha , Hipotálamo/metabolismo , Masculino , Hormônios Estimuladores de Melanócitos/farmacologia , Proteínas do Tecido Nervoso/genética , Nucleobindinas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Cauda , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-MSH analogues, c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by ¹H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO2-C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 ± 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 ± 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 ± 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction.