RESUMO
BACKGROUND: Obesity is a multifactorial chronic disease with a high, increasing worldwide prevalence. Genetic causes account for 7% of the cases in children with extreme obesity. DATA SOURCES: This narrative review was conducted by searching for papers published in the PubMed/MEDLINE, Embase and SciELO databases and included 161 articles. The search used the following search terms: "obesity", "obesity and genetics", "leptin", "Prader-Willi syndrome", and "melanocortins". The types of studies included were systematic reviews, clinical trials, prospective cohort studies, cross-sectional and prospective studies, narrative reviews, and case reports. RESULTS: The leptin-melanocortin pathway is primarily responsible for the regulation of appetite and body weight. However, several important aspects of the pathophysiology of obesity remain unknown. Genetic causes of obesity can be grouped into syndromic, monogenic, and polygenic causes and should be assessed in children with extreme obesity before the age of 5 years, hyperphagia, or a family history of extreme obesity. A microarray study, an analysis of the melanocortin type 4 receptor gene mutations and leptin levels should be performed for this purpose. There are three therapeutic levels: lifestyle modifications, pharmacological treatment, and bariatric surgery. CONCLUSIONS: Genetic study technologies are in constant development; however, we are still far from having a personalized approach to genetic causes of obesity. A significant proportion of the affected individuals are associated with genetic causes; however, there are still barriers to its approach, as it continues to be underdiagnosed. Video Abstract (MP4 1041807 KB).
Assuntos
Leptina , Obesidade Mórbida , Criança , Humanos , Pré-Escolar , Leptina/genética , Estudos Prospectivos , Estudos Transversais , Obesidade , Obesidade Mórbida/genética , Melanocortinas/genéticaRESUMO
Polymorphisms in genes of leptin-melanocortin and insulin pathways have been associated with obesity and type 2 diabetes. We hypothesized that polymorphisms in IRS1, IRS2, MC3R, and MC4R influence metabolic and inflammatory markers and food intake composition in Brazilian subjects. This exploratory pilot study included 358 adult subjects. Clinical, anthropometric, and laboratory data were obtained through interview and access to medical records. The variants IRS1 rs2943634 AËC, IRS2 rs1865434 C>T, MC3R rs3746619 C>A, and MC4R rs17782313 T>C were analyzed by real-time polymerase chain reaction. Food intake composition was assessed in a group of subjects with obesity (n = 84) before and after a short-term nutritional counseling program (9 weeks). MC4R rs17782313 was associated with increased risk of obesity (P = .034). Multivariate linear regression analysis adjusted by covariates indicated associations of IRS2 rs1865434 with reduced low-density lipoprotein cholesterol and resistin, MC3R rs3746619 with high glycated hemoglobin, and IRS1 rs2943634 and MC4R rs17782313 with increased high-sensitivity C-reactive protein (P < .05). Energy intake and carbohydrate and total fat intakes were reduced after the diet-oriented program (P < .05). Multivariate linear regression analysis showed associations of IRS2 rs1865434 with high basal fiber intake, IRS1 rs2943634 with low postprogram carbohydrate intake, and MC4R rs17782313 with low postprogram total fat and saturated fatty acid intakes (P < .05). Although significant associations did not survive correction for multiple comparisons using the Benjamini-Hochberg method in this exploratory study, polymorphisms in IRS1, IRS2, MC3R, and MC4R influence metabolic and inflammatory status in Brazilian adults. IRS1 and MC4R variants may influence carbohydrate, total fat, and saturated fatty acid intakes in response to a diet-oriented program in subjects with obesity.
Assuntos
Polimorfismo Genético , Diabetes Mellitus , Nutrigenômica , Proteínas Substratos do Receptor de Insulina , Obesidade , Carboidratos , Projetos Piloto , Ingestão de Alimentos , Melanocortinas , Ácidos GraxosRESUMO
Introdução A COVID-19 é caracterizada por uma fase viral inicial seguida por uma fase inflamatória. AP1189 é um agonista enviesado da melanocortina com importante ação anti-inflamatória e pró-resolutiva. Nesta dissertação investigamos a segurança e eficácia de AP1189 no tratamento de pacientes com COVID-19 grave. Métodos O ensaio foi composto de duas partes. A primeira parte foi uma fase de braço único de 6 pacientes para avaliar a segurança da administração de AP1189 a pacientes COVID-19. Na segunda parte, 54 pacientes foram randomizados 2:1 para receber tratamento padrão mais AP1189 ou placebo de forma duplo-cega. AP1189 ou placebo pareado foi administrado como uma suspensão oral uma vez ao dia por até 2 semanas a partir do início da oxigenoterapia suplementar. O desfecho primário de eficácia foi o número de dias necessários para que os pacientes alcançassem a recuperação respiratória, definido como um valor de saturação periférica de oxigênio (SpO2) ≥ 93% por 30 min em ar ambiente. Resultados No total, 42 pacientes foram designados no grupo AP1189, enquanto 18 receberam placebo. Todos os pacientes receberam dexametasona como tratamento padrão. O grupo AP1189 levou uma mediana (IQR) de 4 (3,7) dias vs. 6 (4,12) dias com placebo para alcançar a recuperação respiratória (p<0.0001). Os pacientes tratados com AP1189 tiveram menor tempo de internação hospitalar, mediana de 6 dias (4,8), quando comparados ao placebo, 7 dias (5,14) (p<0.0001). O perfil de segurança foi semelhante para AP1189 e placebo. Conclusão O tratamento com AP1189 foi seguro em pacientes COVID-19 graves que já tomavam glicocorticoides e foi eficaz em diminuir o tempo de recuperação respiratória e o tempo de internação hospitalar.
Introduction COVID-19 is characterized by an initial viral phase followed by an inflammatory phase. AP1189 is a biased melanocortin agonist with important anti-inflammatory and pro-resolving action. In this dissertation, we investigated the safety and efficacy of AP1189 in the treatment of patients with severe COVID-19. Methods The trial was composed of two parts. The first part was a 6-patient single-arm phase to evaluate the safety of administering AP1189 to COVID-19 patients. In the second part, 54 patients were randomized 2:1 to receive standard treatment plus AP1189 or placebo in a double-blind fashion. AP1189 or matched placebo was administered as an oral suspension once daily for up to 2 weeks from the start of supplemental oxygen therapy. The primary efficacy endpoint was the number of days required for patients to achieve respiratory recovery, defined as a peripheral oxygen saturation (SpO2) value ≥ 93% for 30 min on room air. Results In total, 42 patients were assigned to the AP1189 group, while 18 received placebo. All patients received dexamethasone as standard treatment. The AP1189 group took a median (IQR) of 4 (3.7) days vs. 6 (4.12) days with placebo to achieve respiratory recovery (p<0.0001). Patients treated with AP1189 had a shorter hospital stay, a median of 6 days (4.8), when compared to placebo, 7 days (5.14) (p<0.0001). The safety profile was similar for AP1189 and placebo. Conclusion Treatment with AP1189 was safe in severe COVID-19 patients who were already taking glucocorticoids and was effective in reducing respiratory recovery time and hospital stay.
Assuntos
Terapêutica , Melanocortinas , COVID-19 , HospitaisRESUMO
A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.
Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.
Assuntos
Humanos , Masculino , Feminino , Peso Corporal/genética , Epigenômica , Genes/genética , Obesidade/genética , Índice de Massa Corporal , Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/genética , Melanocortinas/genética , Receptores para Leptina/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Hipotálamo/fisiopatologia , Obesidade/fisiopatologiaRESUMO
Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.
Assuntos
Adenoma Hipofisário Secretor de ACT , Adenoma , Carcinoma , Genômica , Síndrome de Nelson , Neoplasias Hipofisárias , Adenoma Hipofisário Secretor de ACT/genética , Adenoma/genética , Adenoma/patologia , Hormônio Adrenocorticotrópico , Aurora Quinase A , Carcinoma/genética , Corticotrofos/patologia , Receptores ErbB , Humanos , Melanocortinas , Complexos Multienzimáticos , Nucleotídeos , Neoplasias Hipofisárias/genéticaRESUMO
BACKGROUND: Fitzroya cupressoides, commonly known as alerce, is an endemic conifer unique to southern South America. Alerce wood is renowned for its durability and resistance to biological degradation due to the presence of a particular class of secondary metabolite. Alerce extracts have been used in traditional medicine for different skin lesion treatments. AIMS: To develop a cell culture system to produce alerce extract and evaluate its cytotoxicity and effects on in vitro wound healing. METHODS: Cell cultures and aqueous extracts were prepared from alerce needles. Cytotoxicity was evaluated in keratinocytes (HaCaT line) and melanocites (C32 line) using the XTT assay. Wound healing was assayed with the scratch test in HaCaT cells, using mitomycin C to evaluate the role of cell division in the wound closure. RESULTS: Alerce cell culture extract has a significant effect on wound healing at different concentrations. No positive effects on the viability of normal and cancerous skin cells were observed. These results suggest that alerce extracts stimulate cell division in human skin epidermal cells in the context of wound repair. CONCLUSIONS: Bioactive compounds extracted from alerce cell cultures show promise as ingredients in dermocosmetic formulations, but further clinical studies are required to support these findings at the tissue level.
Assuntos
Extratos Celulares/farmacologia , Cosmecêuticos/farmacologia , Cupressaceae/química , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Técnicas de Cultura de Células , Extratos Celulares/isolamento & purificação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cosmecêuticos/isolamento & purificação , Cupressaceae/citologia , Humanos , Queratinócitos , Melanocortinas , Extratos Vegetais/isolamento & purificação , Testes de Toxicidade AgudaRESUMO
Food intake is tightly regulated by a group of neurons present in the arcuate nucleus of the hypothalamus, which release Pomc-encoded melanocortins, the absence of which induces marked hyperphagia and early-onset obesity. Although the relevance of hypothalamic POMC neurons in the regulation of body weight and energy balance is well appreciated, little is known about the transcription factors that establish the melanocortin neuron identity during brain development and its phenotypic maintenance in postnatal life. Here, we report that the transcription factor NKX2.1 is present in mouse hypothalamic POMC neurons from early development to adulthood. Electromobility shift assays showed that NKX2.1 binds in vitro to NKX binding motifs present in the neuronal Pomc enhancers nPE1 and nPE2 and chromatin immunoprecipitation assays detected in vivo binding of NKX2.1 to nPE1 and nPE2 in mouse hypothalamic extracts. Transgenic and mutant studies performed in mouse embryos of either sex and adult males showed that the NKX motifs present in nPE1 and nPE2 are essential for their transcriptional enhancer activity. The conditional early inactivation of Nkx2.1 in the ventral hypothalamus prevented the onset of Pomc expression. Selective Nkx2.1 ablation from POMC neurons decreased Pomc expression in adult males and mildly increased their body weight and adiposity. Our results demonstrate that NKX2.1 is necessary to activate Pomc expression by binding to conserved canonical NKX motifs present in nPE1 and nPE2. Therefore, NKX2.1 plays a critical role in the early establishment of hypothalamic melanocortin neuron identity and participates in the maintenance of Pomc expression levels during adulthood.SIGNIFICANCE STATEMENT Food intake and body weight regulation depend on hypothalamic neurons that release satiety-inducing neuropeptides, known as melanocortins. Central melanocortins are encoded byPomc, and Pomc mutations may lead to hyperphagia and severe obesity. Although the importance of central melanocortins is well appreciated, the genetic program that establishes and maintains fully functional POMC neurons remains to be explored. Here, we combined molecular, genetic, developmental, and functional studies that led to the discovery of NKX2.1, a transcription factor that participates in the early morphogenesis of the developing hypothalamus, as a key player in establishing the early identity of melanocortin neurons by activating Pomc expression. Thus, Nkx2.1 adds to the growing list of genes that participate in body weight regulation and adiposity.
Assuntos
Melanocortinas/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Fator Nuclear 1 de Tireoide/metabolismo , Animais , Peso Corporal/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo/embriologia , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Central glutamate, melanocortin and corticotropin systems have mediatory role on several physiologic functions in the brain, but their interactions on appetite regulation are not fully elicited. So, the aim of the current study was to determine interaction of the glutamate with melanocortin and corticotropin systems on food intake in 3-h food-deprived (FD3) neonatal meat-type chicken. In experiment 1, chicken intracerebroventricular (ICV) injected (A) phosphate-buffered saline (PBS), (B) glutamate (75 nmol), (C) glutamate (150 nmol) and (D) glutamate (300 nmol). In experiment 2, (A) PBS, (B) astressin-B (CRF1/CRF2 receptors antagonist, 30 µg), (C) glutamate (300 nmol) and (D) astressin-B+glutamate were ICV injected. Experiments 3-5 were similar to experiment 2, except birds were injected with astressin2-B (CRF2 receptor antagonist, 30 µg), SHU9119 (MC3/MC4 receptor antagonist, 0.5 nmol) and MCL0020 (MC4 receptor antagonist, 0.5 nmol) instead of the astressin-B. In experiment 6, the injections were (A) PBS, (B) MTII (MC3/MC4 receptor agonist, 2.5ng), (C) glutamate (75nmol) and (D) MTII+glutamate. Then, cumulative feed intake was recorded at 30, 60 and 120 minutes after injection. According to the results, dose dependent hypophagia observed by ICV injection of the glutamate (75, 150 and 300nmol) compared to control group in neonatal broiler chicken (p 0.05). Co-injection of the astressin-B+glutamate and astressin2-B+glutamate decreased glutamate-induced hypophagia in neonatal broiler chicken (p 0.05). Co-injection of the glutamate+MC3/MC4 receptors antagonist decreased hypophagic effect of the glutamate (p 0.05). These results suggested hypophagic effect of the glutamate mediates via CRF1/CRF2 and MC3/MC4 receptors in chickens.(AU)
Assuntos
Animais , Galinhas/genética , Ingestão de Alimentos , Ácido Glutâmico/análise , Hormônio Adrenocorticotrópico , MelanocortinasRESUMO
Central glutamate, melanocortin and corticotropin systems have mediatory role on several physiologic functions in the brain, but their interactions on appetite regulation are not fully elicited. So, the aim of the current study was to determine interaction of the glutamate with melanocortin and corticotropin systems on food intake in 3-h food-deprived (FD3) neonatal meat-type chicken. In experiment 1, chicken intracerebroventricular (ICV) injected (A) phosphate-buffered saline (PBS), (B) glutamate (75 nmol), (C) glutamate (150 nmol) and (D) glutamate (300 nmol). In experiment 2, (A) PBS, (B) astressin-B (CRF1/CRF2 receptors antagonist, 30 µg), (C) glutamate (300 nmol) and (D) astressin-B+glutamate were ICV injected. Experiments 3-5 were similar to experiment 2, except birds were injected with astressin2-B (CRF2 receptor antagonist, 30 µg), SHU9119 (MC3/MC4 receptor antagonist, 0.5 nmol) and MCL0020 (MC4 receptor antagonist, 0.5 nmol) instead of the astressin-B. In experiment 6, the injections were (A) PBS, (B) MTII (MC3/MC4 receptor agonist, 2.5ng), (C) glutamate (75nmol) and (D) MTII+glutamate. Then, cumulative feed intake was recorded at 30, 60 and 120 minutes after injection. According to the results, dose dependent hypophagia observed by ICV injection of the glutamate (75, 150 and 300nmol) compared to control group in neonatal broiler chicken (p 0.05). Co-injection of the astressin-B+glutamate and astressin2-B+glutamate decreased glutamate-induced hypophagia in neonatal broiler chicken (p 0.05). Co-injection of the glutamate+MC3/MC4 receptors antagonist decreased hypophagic effect of the glutamate (p 0.05). These results suggested hypophagic effect of the glutamate mediates via CRF1/CRF2 and MC3/MC4 receptors in chickens.