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1.
Med Sci (Paris) ; 36(10): 859-865, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026327

RESUMO

Obesity is a complex, multifactorial disorder. About 5% of obese patients actually present with a monogenic form of obesity where only one mutation is sufficient to cause the disease. So far, the genes that have been found to be mutated in these monogenic forms play a key role in the leptin/melanocortin pathway which is mainly active in the hypothalamus and which regulates food intake and energy expenditure. Our laboratory has recently reported a novel monogenic form of obesity due to MRAP2 deficiency where, contrary to previously described monogenic forms of obesity, the carriers presented with hyperglycemia and hypertension in addition to obesity, suggesting that MRAP2 might play a pleiotropic role in metabolic tissues, in addition to its role in brain control of food intake and energy expenditure.


Assuntos
Regulação do Apetite/genética , Obesidade/genética , Animais , Predisposição Genética para Doença , Humanos , Leptina/genética , Leptina/metabolismo , Mutação/fisiologia , Obesidade/patologia , Obesidade/terapia , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
2.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
3.
Life Sci ; 260: 118344, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853651

RESUMO

Pregabalin (PGB) drug abuse is common among the youth. It substituted tramadol before its recent schedule as a controlled drug since April 2019. PGB is an antiepileptic drug acting on the central nervous system. It blocks calcium channels regulating the action of neurotransmitters and causing prolonged depolarization. The present study aimed to investigate the toxic effect of long term pregabalin abuse on the reproductive function and body weight in both male and female albino rats and to evaluate the ameliorative effect of wheat germ oil (WGO). Forty-eight rats were randomly divided into eight groups. The first four groups were males and they were treated as follows: control group (1.5 mL saline), WGO group (1.5 mL L/kg), PGB group (300 mg/kg), and protective group (PGB + WGO). All doses were administrated once per day for 60 days by gastric gavage. The second four groups were females. They were divided and treated the same as the male groups. Pregabalin caused significant weight loss, decreased serum triglyceride level, and increased leptin gene expression in all rats. PGB affected male rats reproduction by decreasing total testosterone serum level and inhibiting spermatogenesis. Reproductive toxicity in females was caused by decreasing pituitary steroids, increasing gonadal hormones, and increasing the number of atretic ovarian follicles. Mechanism of toxicity may be attributed to the PGB oxidative stress effect that induced apoptosis and caused diffuse gonadal atrophy. WGO showed a protective effect on PGB induced toxicity as all measured parameters were relatively improved.


Assuntos
Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Leptina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Óleos Vegetais/farmacologia , Pregabalina/toxicidade , Reprodução/efeitos dos fármacos , Animais , Caspase 3/genética , Feminino , Leptina/genética , Óleos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Ratos
4.
Rev. Saúde Pública Paraná (Online) ; 3(1): 120-128, 08/07/2020.
Artigo em Português | Coleciona SUS, CONASS, SESA-PR | ID: biblio-1119437

RESUMO

Mutações na leptina ou em seu receptor causam a denominada obesidade mórbida relacionada à deficiência de leptina congênita, capaz de ser revertida eficazmente pela terapia com leptina. Nesse sentido, o objetivo desse estudo foi realizar uma revisão integrativa da literatura relacionada a evidências de Associação entre polimorfismos no gene/receptor da leptina avaliados por meio da reação em cadeia de polimerase e presença de obesidade. Foram incluídos artigos publicados em língua portuguesa, inglesa e espanhola, na íntegra, entre 2009 e 2019, que respondessem a problemática da pesquisa. A busca deu-se nas bases de dados: SCIELO, PUBMED e LILACS, a partir dos descritores PCR, Leptin, Obesity; a amostra final foi constituída de 09 artigos. Concluiu-se que polimorfismos no gene codificador/receptor desse hormônio regulador da ingestão de alimentos e energia metabólica podem ser um dos mais promissores candidatos no que diz respeito a biomarcadores da obesidade. (AU)


Mutations in leptin or in its receptor cause morbid obesity related to congenital leptin deficiency that can be effectively reversed with leptin therapy. In this sense, the aim of the study is to perform an integrative literature review related to evidence of the association between gene/leptin receptor polymorphisms, evaluated through polymerase chain reaction, and the presence of obesity. Publications in Portuguese, English and Spanish, in full, between 2009 and 2019, which responded to the research problem were included. The search was made in the following databases: SCIELO, PUBMED and LILACS, using the descriptors PCR, Leptin, Obesity; the final sample consisted of 09 articles. It is concluded that polymorphisms of coding gene/receptor of this food intake regulating hormone and metabolic energy may be more promising candidates for a biological risk of obesity. (AU)


Assuntos
Humanos , Masculino , Feminino , Obesidade Mórbida/genética , Reação em Cadeia da Polimerase , Leptina/genética , Polimorfismo de Nucleotídeo Único/genética
5.
Gene ; 754: 144846, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32512158

RESUMO

OBJECTIVES: Obesity is a major risk factor in aetiology of type 2 diabetes mellitus (T2DM). Leptin (LEP) is an anti-obesity hormone which regulates food intake, energy expenditure and glucose metabolism. The genetic variants in leptin and leptin receptor gene (LEPR) may play major role in the pathogenesis of T2DM and obesity. The current study aimed to investigate the association of polymorphisms in LEP (rs7799039, -2548G/A and rs2167270, 19G/A) and LEPR (rs1137101, 668A/G) gene with type 2 diabetes in North Indian Punjabi population. METHODS: A total of 817 subjects were included for the present case-control study, consisting of 417 T2DM patients and 400 healthy controls. The anthropometric, physiometric and biochemical measurements were taken from all the subjects. The genotyping of LEP and LEPR gene variants were carried out by polymerase chain reaction based restriction fragment length polymorphism method (PCR-RFLP), followed by genotyping of 10% of the samples for each polymorphism by Sanger sequencing method for quality control measurement. RESULTS: The risk genotype frequencies were found to be significantly higher in T2DM cases than control subjects (rs7799039, p = 0.001; rs2167270, p = 0.019 and rs1137101, p = 0.003). Under recessive genetic model LEPrs7799039 and LEPRrs1137101 polymorphism conferred 3.4 and 2.1 fold risk towards the development of T2DM after adjustment of various covariates (OR = 3.44, 95%CI: 1.768-6.681, p = 0.001 and OR: 2.12, 95%CI: 1.256-3.569, p = 0.005, respectively). In the stratified analysis of LEP variant rs7799039 by age, gender, BMI and alcohol use, a significantly increased risk of T2DM was found in female, BMI ≥ 23 and never drinking subgroups. However, in the LEPR variant rs1137101, significantly increased risk of T2DM was observed in age <50, male, BMI ≥ 23 and never drinking subgroup. The A-G haplotype combination of rs7799039A and rs2167270G conferred significant 2 fold risk towards T2DM (OR = 2.35, 95%CI: 1.34-4.12, p = 0.002). In control group, the genetic variants rs7799039 and rs1137101 were significantly associated with levels of random blood sugar and low density lipoprotein cholesterol levels. CONCLUSION: The present study revealed the association of LEP rs7799039 and LEPR rs1137101 with type 2 diabetes mellitus, which suggest its predominant role in the estimation of type 2 diabetes mellitus in North Indian Punjabi population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença , Leptina/genética , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptores para Leptina/genética , Adulto , Idoso , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Genótipo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
PLoS One ; 15(6): e0234465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544194

RESUMO

Obesity leads a crucial importance in metabolic disorders, as well as type 2 diabetes mellitus. Our present study was designed to assess the potential role of irisin, adiponectin, leptin and gene polymorphism of PNPLA3, leptin and adiponectin as predictive markers of diabetes associated with obesity. One hundred eighty subjects were distributed to three groups including; healthy non-diabetic non obese volunteers as a control group, diabetic non obese group, and diabetic obese group (n = 60 for each group). Fasting blood samples of all groups were collected to determine fasting blood glucose, insulin levels, insulin resistance, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triacylglycerol, irisin, adiponectin, leptin; as well as, polymorphism of PNPLA3, adiponectin and leptin. The results showed that glucose, insulin resistance, total cholesterol, irisin, leptin, LDL-C, triacylglycerol concentrations were significantly increased, however, insulin, HDL-C, adiponectin were significantly decreased in diabetic obese patients in relation to diabetic non-obese patients as well as in healthy volunteers. The polymorphism of PNPLA3 rs738409 was linearly related to irisin and leptin but was not related with circulating concentrations of adiponectin. We concluded that increased irisin and leptin levels can predict the insulin resistance in obese patients. Moreover, patients who have mutant genotype of PNPLA3 I148 gene (rs738409) C>G, ADIPOQ gene (rs266729) G>C and LEP gene (rs2167270) G>A showed a significant higher susceptibility rate for DM in obese people than those with wild type. This could be considered as an adjustable retort to counter the impact of obesity on glucose homeostasis.


Assuntos
Adiponectina/genética , Diabetes Mellitus Tipo 2/etiologia , Predisposição Genética para Doença , Resistência à Insulina/genética , Leptina/genética , Lipase/genética , Proteínas de Membrana/genética , Obesidade/complicações , Obesidade/genética , Adiponectina/sangue , Adulto , Feminino , Fibronectinas/sangue , Fibronectinas/genética , Marcadores Genéticos , Humanos , Leptina/sangue , Lipase/sangue , Masculino , Proteínas de Membrana/sangue , Polimorfismo Genético , Adulto Jovem
7.
PLoS One ; 15(5): e0227527, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374776

RESUMO

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.


Assuntos
Diabetes Mellitus Tipo 2/genética , Degeneração do Disco Intervertebral/genética , Leptina/genética , Obesidade/genética , Receptores para Leptina/genética , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Obesidade/metabolismo , Obesidade/patologia , Receptores para Leptina/deficiência , Caracteres Sexuais , Transdução de Sinais/genética , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
8.
Nat Commun ; 11(1): 1914, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313051

RESUMO

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.


Assuntos
Autofagia/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Neurogênese/fisiologia , Adiposidade , Animais , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Ingestão de Alimentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Comportamento Alimentar , Homeostase , Hiperfagia/metabolismo , Leptina/genética , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Neuroendocrinologia , Neurogênese/efeitos dos fármacos , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Ácido Tauroquenodesoxicólico
9.
J Anim Sci ; 98(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32277699

RESUMO

Leptin genotypes can be identified as homozygous normal (CC), homozygous mutant (TT), and heterozygous (CT) based on a single-nucleotide polymorphism in exon 2 of the leptin gene, which has been associated with feed intake and fat deposition in cattle. The experiment was designed as 2 × 2 × 2 factorial with three main factors: (1) genotype (CT or TT) and diets fed 2) with or without triticale dried distiller's grains with solubles (DDG), and 3) with either flaxseed (FS) or high-oleate sunflower seed (SS). Evaluations included growth performance, subcutaneous fat deposition, adipocyte cellularity, meat quality, and fatty acid (FA) profile of various depots. Beef steers (n = 40, 459 ± 31 kg) of either CT or TT genotypes were housed in individual pens with ad libitum access to one of the four diets: 75% steam-rolled barley + 10% barley silage with 10% FS or SS (non-DDG diets, NDG) and 46.5% barley + 10% barley silage + 30% DDG, with 8.5% FS or SS, all on a dry matter basis. Growth performance, ultrasound subcutaneous fat thickness, rib eye area (REA), and plasma FA were measured prior to and during the finishing period. At slaughter, samples of subcutaneous fat, perirenal fat, and Longissimus thoracis (LT) muscle were collected for FA analysis and carcass and meat quality were measured. Compared with CT cattle, TT tended to have less (P = 0.06) C18:2-c9,t11 (rumenic acid) in plasma and subcutaneous fat and a greater proportion (P < 0.05) of C18:0 in subcutaneous, perirenal, and LT fat. Cattle with TT genotype also tended (P < 0.1) to have more total saturated and less unsaturated (USFA) and monounsaturated fats (MUFA) and had less (P = 0.04) linoleic acid in LT. Ultrasound fat thickness, REA, and average diameter of adipocytes in subcutaneous fat at 12 wk were not affected (P > 0.39) by genotype. Generally, carcass and meat quality were similar (P > 0.1) among diets, although adding FS tended to increase (P = 0.06) total USFA of subcutaneous fat including omega-3 FA (P < 0.001). For the high-fat diets evaluated, CT cattle would have more potential to produce beef with enhanced health benefits than would TT cattle.


Assuntos
Ração Animal/análise , Bovinos/fisiologia , Ácidos Graxos/análise , Leptina/genética , Carne Vermelha/normas , Adipócitos/metabolismo , Animais , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Dieta/veterinária , Linho , Genótipo , Helianthus , Hordeum , Masculino , Ácido Oleico/análise , Sementes , Silagem/análise , Gordura Subcutânea/química , Triticale
10.
Diabetes ; 69(5): 823-829, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312898

RESUMO

The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed "leptin resistance" phenomenon. Our recent data in this area prompt us to call for a conceptual shift. This shift entails a model in which a reduction of bioactive leptin levels in the context of obesity triggers a high degree of leptin sensitization and improved leptin action, both centrally and peripherally. Put another way, hyperleptinemia per se causes leptin resistance and associated metabolic disorders. In this perspective, we briefly discuss the underlying conceptual steps that led us to explore partial leptin reduction as a viable therapeutic avenue. We hope this discussion will contribute to potential future applications of partial leptin reduction therapy for the treatment of obesity and type 2 diabetes.


Assuntos
Leptina/metabolismo , Leptina/farmacologia , Obesidade/sangue , Animais , Evolução Biológica , Humanos , Leptina/sangue , Leptina/genética , Camundongos , Obesidade/metabolismo , Obesidade/terapia
11.
Poult Sci ; 99(3): 1409-1420, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32115028

RESUMO

Lysine is the second most limiting amino acid after methionine and is considered the most limiting amino acid for growth in poultry. Lysine requirement for broiler chickens has changed over the years. Leptin and adiponectin represent 2 adipokines that mediate metabolism by eliciting satiety effects whereas ghrelin peptide hormone influences appetite. We hypothesize that this affects growth performance of chicks. This study evaluates the effect of varying dietary lysine homeostasis on performance of broiler chickens through satiety- and appetite-mediating hormones. In 3 replications, 270 one-day-old chicks were reared for 8 wk feeding on diets comprising 0.85, 1.14, and 1.42% lysine during the starter period and 0.75, 1.00, and 1.25% lysine during the grower period. These concentrations of lysine represent 75% (low lysine), 100% (control), and 125% (high lysine) of National Research Council recommendation for broiler chickens. Feed and water were provided for ad libitum consumption. At 8 wk of age, liver, pancreas, brain, and hypothalamus tissues were collected from 18 birds randomly selected from each treatment, snap frozen in liquid nitrogen, and stored at -80°C until use. Total RNA was extracted, and cDNA was synthesized for quantitative real-time PCR assays. Low lysine concentration caused slow growth and high mortality. There was significant upregulation of ghrelin in the hypothalamus and pancreas, and leptin and adiponectin in the hypothalamus and liver, and downregulation of ghrelin in the intestines. At low lysine concentrations, adiponectin was not expressed in both pancreas and intestines. High lysine concentration exhibited increased growth, upregulation of ghrelin in the liver, and downregulation of ghrelin in the intestines, and both adiponectin and leptin in the liver. The expression of ghrelin was negatively correlated with the expression of adiponectin and leptin (P < 0.05) in the liver, hypothalamus, and pancreas. Expression of leptin was positively correlated with adiponectin in the hypothalamus and liver (P < 0.05), exhibiting satiety effects when the concentrations of lysine were low.


Assuntos
Apetite/genética , Galinhas/fisiologia , Lisina/metabolismo , Neuropeptídeos/genética , Hormônios Peptídicos/genética , Saciação , Adiponectina/genética , Adiponectina/metabolismo , Ração Animal/análise , Animais , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Regulação para Baixo , Perfilação da Expressão Gênica/veterinária , Grelina/genética , Grelina/metabolismo , Homeostase , Leptina/genética , Leptina/metabolismo , Lisina/administração & dosagem , Neuropeptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Distribuição Aleatória , Regulação para Cima
12.
Gene ; 736: 144420, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007585

RESUMO

Leptin has been proved to play critical roles in energy metabolism, body weight regulation, food intake, reproduction and immunity in mammals. However, its roles are still largely unclear in fish. Here, we report two leptin genes (lepA and lepB) from the Northern snakehead (Channa argus) and their transcriptions in response to different feeding status. The snakehead lepA is 781 bp in length and contains a 480 bp open reading frame (ORF) encoding a 159-aa protein, while the snakehead lepB is 553 bp in length and contains a 477 bp ORF encoding a 158-aa protein. Multi-sequences alignment, three-dimensional (3D) model prediction, syntenic and genomic comparison, and phylogenetic analysis confirm two leptin genes are widely existing in teleost. Tissue distribution revealed that the two leptin genes exhibit different patterns. In a post-prandial experiment, the hepatic lepA and brain lepB showed a similar transcription pattern. In a long-term (2-week) fasting and refeeding experiment, the hepatic lepA and brain lepB showed a similar transcription change pattern induced by food deprivation stimulation but differential changes after refeeding. These findings suggest snakehead lepA and lepB are differential both in tissue distribution and molecular functions, and they might play as an important regulator in energy metabolism and food intake in fish, respectively.


Assuntos
Jejum/fisiologia , Comportamento Alimentar/fisiologia , Peixes/genética , Leptina/genética , Fases de Leitura Aberta/genética , Transcrição Genética/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Peso Corporal/genética , Genômica/métodos , Filogenia , Alinhamento de Sequência , Distribuição Tecidual/genética
13.
Rev Soc Bras Med Trop ; 53: e20190388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049202

RESUMO

INTRODUCTION: Leptin (LEP) is a peptide hormone that acts via leptin receptor (LEPR) binding. Genetic evidence from different human populations has implicated LEP/LEPR in the pathogenesis of coronary artery disease (CAD), and suggests that certain LEP/LEPR gene polymorphisms may increase the risk of CAD. The aim of this study was to assess two single nucleotide polymorphisms (SNPs) in LEP genes (rs2167270 and rs7799039) and two in LEPR genes (rs6588147, rs1137100) for association with CAD. METHODS: We enrolled 271 North Chinese Han CAD patients, and 113 healthy age- and sex-matched controls. Genomic DNA was extracted from whole blood, and the four SNPs were assessed using a MassArray system. RESULTS: The G allele frequency at rs2167270 was significantly higher among CAD cases than among controls. The AG genotype at rs7799039 was associated with a significantly decreased risk of CAD unlike the AA genotype used as the reference. The A allele was significantly associated with the CAD patient group. Interestingly, statistically significant differences in genotype and allele frequency at LEP rs2167270 and rs7799039 existed among females but not among males. CONCLUSIONS: The current study detected a significant association between genetic variations at LEP rs7799039 and rs2167270 and the risk of CAD in a north Chinese population, and revealed that LEP rs2167270 and rs7799039 gene polymorphisms might act as predisposing factors for CAD.


Assuntos
Doença da Artéria Coronariana/genética , Leptina/genética , Receptores para Leptina/genética , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
14.
J Endocrinol ; 245(1): 165-178, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32053493

RESUMO

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor ß (ERß). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERß-null (ßKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and ßKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and ßKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERß in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). ßKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERß in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERß may mediate protective metabolic benefits.


Assuntos
Adiposidade/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Resistência à Insulina/genética , Ovariectomia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal/genética , Metabolismo Energético/genética , Receptor alfa de Estrogênio/deficiência , Receptor beta de Estrogênio/deficiência , Feminino , Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética
15.
Indian J Pediatr ; 87(2): 105-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31925720

RESUMO

OBJECTIVES: To screen for variants in the MC4R and LEP genes in 46 patients with clinical suspicion of non-syndromic early onset severe obesity (NEOSO). METHODS: Children with early onset obesity satisfying WHO criteria of obesity were studied. The MC4R and LEP genes were sequenced using a PCR amplicon based NGS on Illumina MiSeq next generation sequencer using an in-house developed protocol. RESULTS: Of the 46 children tested, four were found to have novel pathogenic/likely-pathogenic variants (one in the MC4R gene and three in the LEP gene). In three out of the 4 families, the presence of the variants was confirmed using standard bidirectional capillary sequencing in the probands. CONCLUSIONS: Four children with novel likely pathogenic variants in the MC4R and LEP genes are reported. Genetic analysis is crucial in children with early onset obesity and should be considered.


Assuntos
Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leptina/genética , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/genética , Receptor Tipo 4 de Melanocortina/genética , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Lactente , Masculino
16.
Sci Rep ; 10(1): 999, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969648

RESUMO

The reproductive phase-dependent and sex-related differential expression of leptin (lep) and its receptor (lepr) in primary and secondary lymphoid organs of a highly nutritive economically important Channa punctata preempts the involvement of sex steroids in modulating intra-immuno-leptin system. This hypothesis was strengthened when plasma testosterone (T) and estradiol (E2) levels in male and female fish of reproductively active spawning and quiescent phases were correlated with lep and lepr expression in their immune organs. Splenic lep and lepr showed a negative correlation with T in both male and female, while with E2 there was a positive correlation in male and negative in female C. punctata. In head kidney, a contrasting correlation was observed as compared to spleen. To validate the implication of sex steroids in regulating leptin system in immune organs, in vivo and in vitro experiments were performed with DHT and E2. Upon administration, lep and lepr expression in tissues of either sex was downregulated. In addition, in vitro results with either of the sex steroids exemplified their direct involvement. Overall, this study, for the first time, reports correlation between sex steroids and transcript expression of leptin system in immune organs of a seasonally breeding vertebrate.


Assuntos
Estradiol/sangue , Peixes/fisiologia , Leptina/metabolismo , Receptores para Leptina/metabolismo , Reprodução/fisiologia , Testosterona/sangue , Animais , Feminino , Regulação da Expressão Gênica , Leptina/genética , Masculino , Receptores para Leptina/genética , Caracteres Sexuais
17.
Int J Mol Sci ; 21(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940810

RESUMO

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5+0-11+6, n = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O2). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development.


Assuntos
Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/metabolismo , Obesidade/metabolismo , Complicações na Gravidez/metabolismo , Adulto , Proteína BRCA1/genética , Proteínas de Ciclo Celular/genética , Feminino , Glucose/metabolismo , Humanos , Interleucina-6/metabolismo , Leptina/genética , Leptina/metabolismo , Obesidade/genética , Oxigênio/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Exp Eye Res ; 191: 107916, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31926133

RESUMO

Orbital venous malformations (OVMs) are the most common benign orbital vascular disorders in adults and are characterized as enlarging encapsulated vascular neoplasms. These painless lesions grow slowly and become symptomatic with proptosis or visual disturbance. However, the pathogenic mechanism and diagnostic markers of OVMs remain poorly understood. To identify potential pathways involved in OVM formation, a cDNA microarray analysis was conducted with OVM samples and normal vascular tissues. These data were deposited in the National Omics Data Encyclopedia (NODE) database (accession number: OER033009). These pathway expression data were further confirmed by reverse transcription qPCR (RT-qPCR) in an OVM cohort. To explore the diagnostic markers in OVM, an angiogenesis antibody array was analyzed. The altered factors were further validated by enzyme-linked immunosorbent assay (ELISA) in the OVM cohort. Transcriptome screening revealed upregulated autophagy and VEGF pathways and downregulated Hippo, Wnt, hedgehog and vascular smooth muscle contraction signaling pathways in OVM samples. Furthermore, plasma EGF (p < 0.001) and Leptin (p < 0.01) levels were significantly elevated in OVM patients. Here, for the first time, we revealed the transcriptional background and plasma diagnostic markers in OVM, providing a novel understanding of OVM pathogenesis and facilitating the early diagnosis of OVM.


Assuntos
Proteínas Angiogênicas/genética , Fator de Crescimento Epidérmico/genética , Leptina/genética , Órbita/irrigação sanguínea , Malformações Vasculares/genética , Veias/anormalidades , Adolescente , Adulto , Autofagia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Marcadores Genéticos , Ensaios de Triagem em Larga Escala , Humanos , Hibridização In Situ , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Órbita/diagnóstico por imagem , Reação em Cadeia da Polimerase em Tempo Real , Malformações Vasculares/diagnóstico por imagem , Veias/diagnóstico por imagem
19.
Adipocyte ; 9(1): 24-34, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31989870

RESUMO

Insulin plays an important role during adipogenic differentiation of animal preadipocytes and the maintenance of mature phenotypes. However, its role and mechanism in dedifferentiation of adipocyte remains unclear. This study investigated the effects of insulin on dedifferentiation of mice adipocytes, and the potential mechanisms. The preadipocytes were isolated from the subcutaneous white adipose tissue of wild type (WT), TNFα gene mutant (TNFα-/-), leptin gene spontaneous point mutant (db/db) and TNFα-/-/db/db mice and were then induced for differentiation. Interestingly, dedifferentiation of these adipocytes occurred once removing exogenous insulin from the adipogenic medium. As characteristics of dedifferentiation of the adipocytes, downregulation of adipogenic markers, upregulation of stemness markers and loss of intracellular lipids were observed from the four genotypes. Notably, dedifferentiation was occurring earlier if the insulin signal was blocked. These dedifferentiated cells regained the potentials of the stem cell-like characteristics. There is no significant difference in the characteristics of the dedifferentiation between the adipocytes. Overall, the study provided evidence that insulin plays a negative regulatory role in the dedifferentiation of adipocytes. We also confirmed that both dedifferentiation of mouse adipocytes, and effect of the insulin on this process were independent of the cell genotypes, while it is a widespread phenomenon in the adipocytes.


Assuntos
Adipócitos Brancos/citologia , Insulina/farmacologia , Leptina/genética , Receptores para Leptina/genética , Fator de Necrose Tumoral alfa/genética , Adipócitos Brancos/metabolismo , Animais , Biomarcadores/análise , Desdiferenciação Celular , Células Cultivadas , Meios de Cultura/química , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Camundongos , Mutação Puntual , Cultura Primária de Células , Receptores para Leptina/metabolismo
20.
Int J Mol Sci ; 21(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947745

RESUMO

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5'-C-phosphate-G-3' (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (ß = -2.69, p = 0.05) and fat distribution (ß = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (ß = -0.01, p = 0.04) and neonatal leptinemia (ß = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.


Assuntos
Metilação de DNA , Diabetes Gestacional/genética , Hiperglicemia/genética , Leptina/genética , Obesidade/etiologia , Adiposidade , Adulto , Pré-Escolar , Diabetes Gestacional/metabolismo , Epigênese Genética , Feminino , Sangue Fetal/metabolismo , Loci Gênicos , Humanos , Hiperglicemia/metabolismo , Recém-Nascido , Leptina/metabolismo , Masculino , Obesidade/genética , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Adulto Jovem
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