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1.
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
2.
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
3.
Cell Physiol Biochem ; 53(5): 851-864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31714043

RESUMO

BACKGROUND/AIMS: The growth promoting effect of lysine and betaine as well as the expression of candidate genes reflecting their efficacy, such as ghrelin, leptin, Growth Hormone Secretagogue Receptor (GHS-R), Insulin like Growth Factor (IGF- 1) and Growth Hormone Releasing Hormone (GHRH) was examined in Labeo rohita fingerlings. METHODS: One hundred eighty healthy juveniles from a homologous population were randomly distributed to 15 rectangular tanks of 150 litres capacity. The experiment was carried out for 60 days with five treatment groups consisting T1 (0.25% Betaine), T2 (0.5% Betaine), T3 (0.75% Lysine) and T4 (1.5% Lysine) and control group. The experiment was carried out for 60 days with five treatment groups consisting T1 (0.25% Betaine), T2 (0.5% Betaine), T3 (0.75% Lysine) and T4 (1.5% Lysine) and control group. At the end of trial, the growth parameters such as weight gain, SGR, PER were estimated from the weight of the triplicate groups. The digestive, metabolic and antioxidant enzymes were analysed using spectrophotometric methods. The intestine, brain and liver were sampled from the treatments and expression of different genes ghrelin, leptin, GHSR, IGF-1 and GHRH was also performed by realtime PCR. RESULTS: A significant (P<0.05) increase in weight gain, SGR, PER and lowest FCR was found in T4 group which was significantly (p < 0.05) different from other experimental groups. The highest mRNA expression levels of expression were found in T4 group which was similar to that of ghrelin gene mRNA of T2 group. The significantly (p<0.05) highest GHSR, GHRH and IGF-1 gene expression levels were found in T4 treatment group compared to other groups. CONCLUSION: The present study reveals that the lysine and betaine stimulate growth and expression of ghrelin GHRH, GHS-R and IGF-1 genes. The increase of IGF-I mRNA expression with lysine and betaine supplementation revealed that these compounds act as growth modulators. However, lysine was found to be a more potent modulator of growth compared to betaine.


Assuntos
Betaína/farmacologia , Cyprinidae/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lisina/farmacologia , Ração Animal , Animais , Catalase/metabolismo , Cyprinidae/crescimento & desenvolvimento , Grelina/genética , Grelina/metabolismo , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Leptina/genética , Leptina/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Superóxido Dismutase/metabolismo
4.
Nat Commun ; 10(1): 4448, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575865

RESUMO

Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6-12 months (rs2767486, P6m = 2.0 × 10-21, ß6m = 0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P1.5y = 1.3 × 10-8, ß1.5y = 0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Genômica , Receptores para Leptina/genética , Adenilil Ciclases/genética , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Loci Gênicos , Genótipo , Homeostase , Humanos , Lactente , Leptina/sangue , Leptina/genética , Masculino , Noruega , Fenótipo , Polimorfismo de Nucleotídeo Único
5.
Int J Mol Sci ; 20(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615150

RESUMO

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.


Assuntos
Metabolismo Energético/genética , Grelina/genética , Peptídeo YY/genética , Pró-Opiomelanocortina/genética , Animais , Depressores do Apetite/farmacologia , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Grelina/sangue , Hipotálamo/metabolismo , Insulina/sangue , Insulina/genética , Lactação , Leptina/sangue , Leptina/genética , Metilação/efeitos dos fármacos , Peptídeo YY/sangue , Gravidez , Pró-Opiomelanocortina/sangue , RNA Mensageiro/genética , Ratos , Vitamina B 12/genética , Vitamina B 12/farmacologia
6.
World J Gastroenterol ; 25(33): 4904-4920, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543682

RESUMO

BACKGROUND: The trans-fat containing AMLN (amylin liver non-alcoholic steatohepatitis, NASH) diet has been extensively validated in C57BL/6J mice with or without the Lepob/Lepob (ob/ob) mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH. Due to a recent ban on trans-fats as food additive, there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice. AIM: To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat. METHODS: Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat (Primex shortening) substituted by equivalent amounts of palm oil [Gubra amylin NASH, (GAN) diet] for 8, 12 and 16 wk. C57BL/6J mice were fed the same diets for 28 wk. AMLN and GAN diets had similar caloric content (40% fat kcal), fructose (22%) and cholesterol (2%) level. RESULTS: The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance. Biopsy-confirmed steatosis, lobular inflammation, hepatocyte ballooning, fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet. C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets. CONCLUSION: Substitution of Primex with palm oil promotes a similar phenotype of biopsy-confirmed NASH in ob/ob and C57BL/6J mice, making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.


Assuntos
Modelos Animais de Doenças , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Óleo de Palmeira/efeitos adversos , Animais , Biópsia , Dieta Hiperlipídica/efeitos adversos , Humanos , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/patologia , Ácidos Graxos Trans/efeitos adversos
7.
BMC Med Genet ; 20(1): 152, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488071

RESUMO

BACKGROUND: Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. METHODS: We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands. RESULTS: We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome. CONCLUSIONS: Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.


Assuntos
Consanguinidade , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Obesidade Pediátrica/genética , Síndrome de Bardet-Biedl/genética , Índice de Massa Corporal , Pré-Escolar , Códon sem Sentido , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Leptina/genética , Masculino , Mutação , Paquistão , Obesidade Pediátrica/fisiopatologia , Linhagem , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética
8.
BMC Complement Altern Med ; 19(1): 246, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488172

RESUMO

BACKGROUND: Yangkyuksanwha-tang (YST) is an herbal medicine based on Sasang constitutional medicine (SCM) and is widely used in Korean traditional medicine. The aim of the study was to evaluate the effect of YST on obesity in high-fat diet (HFD)-induced obese mice. METHODS: We induced obesity in C57bl/6 J mice using a HFD, and then orally administered 300 mg/kg YST for 6 weeks. We measured body weight, food efficiency, organ and fat weight, serum biochemical parameters, and obesity-related gene expression, and carried out histological analysis at the end of the experimental period. RESULTS: YST significantly reduced the absolute body weight and food efficiency ratio. The serum, aminotransferase, glucose, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels were significantly lower in the YST-treated group than in the control group, whereas the high-density lipoprotein-cholesterol level in the YST-treated group was significantly higher. The YST-treated group also showed a significant reduction in regional fatty tissues and the absolute weight of various organs. We also observed a significantly reduced expression of AP2/FABP4, C/EBP-ß, leptin, and SREBP1c/ADD1 mRNA, and significantly increased expression of UCP-2 and adiponectin mRNA in adipose tissue in the YST-treated group. YST also decreased the lipid droplet size and lipid accumulation in the liver, as well as adipocyte size in epididymal adipose tissue. At the dose tested, YST was non-toxic to the liver and kidneys of the mice. CONCLUSION: The results imply that YST has anti-obesity effects in obesity-induced mice. Although the number of experimental animals was limited and the drug effects concern mice, rather than humans, which have different constitutions, the study has valuable implications with respect to the general effects of YST.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , HDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Medicina Tradicional Coreana , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Extratos Vegetais/química , Plantas Medicinais/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
9.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514326

RESUMO

In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian leptin and TNF is limited and they are absent or lowly expressed in adipose, respectively. Employing radiation-hybrid mapping and FISH-TSA, we mapped TNF and its syntenic genes to chicken chromosome 16 within the major histocompatibility complex (MHC) region. This mapping position suggests that avian TNF has a role in regulating immune response. To test its possible interaction with leptin within the immune system and beyond, we compared the transcription patterns of TNF, leptin and their cognate receptors obtained by meta-analysis of GenBank RNA-seq data. While expression of leptin and its receptor (LEPR) were detected in the brain and digestive tract, TNF and its receptor mRNAs were primarily found in viral-infected and LPS-treated leukocytes. We confirmed leptin expression in the duodenum by immunohistochemistry staining. Altogether, we suggest that whereas leptin and TNF interact as adipokines in mammals, in birds, they have distinct roles. Thus, the interaction between leptin and TNF may be unique to mammals.


Assuntos
Galinhas/genética , Mapeamento Cromossômico , Digestão , Regulação da Expressão Gênica , Leptina/genética , Mamíferos/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Galinhas/metabolismo , Duodeno/metabolismo , Feminino , Leptina/metabolismo , Metáfase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Mapeamento de Híbridos Radioativos , Receptores para Leptina/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Sintenia/genética , Fator de Necrose Tumoral alfa/genética
10.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509948

RESUMO

As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Polipeptídeo Inibidor Gástrico/metabolismo , Leptina/deficiência , Obesidade/metabolismo , Animais , Polipeptídeo Inibidor Gástrico/sangue , Polipeptídeo Inibidor Gástrico/genética , Expressão Gênica , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/genética , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo
11.
Gen Comp Endocrinol ; 283: 113240, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394085

RESUMO

Leptin is primarily considered a peripheral satiety hormone and is also found to perform important roles in energy homeostasis in vertebrates ranging from fish to mammals. The liver is a major source of leptin production in teleost fish. Using goldfish as a model, a previous report by our group illustrated the positive regulation of leptin mRNA levels by treatment with the hyperglycemic hormone glucagon, and our present study provided evidence for the negative regulation of hepatic leptin-AI and leptin-AII transcripts through the administration of the hypoglycemic hormone insulin. This study is the first to demonstrate changes in the hepatopancreatic insulin, glucagon, leptin-AI and leptin-AII mRNA levels in goldfish during fasting and refeeding. Insulin was found to be effective in suppressing leptin-AI and leptin-AII transcript levels in goldfish liver via both in vivo intraperitoneal injection and in vitro cell incubation approaches. Only the insulin receptor, not the IGF-I receptor, was involved in insulin-inhibited leptin mRNA level. The suppression of leptin levels by insulin was caused by the activation of MKK3/6/p38MAPK and MEK1/2/Erk1/2 cascades. Insulin treatment could eliminate the stimulation of glucagon on leptin mRNA level. Our study describes the regulation and signal transduction mechanism of insulin on leptin mRNA levels in the goldfish liver, suggesting that the leptin function in fish is speculated to be not only an anorexigenic factor but also a metabolic mediator. This also supports the hypothesis that the poikilothermal fish use a passive survival strategy during the periods of food deprivation, which is mediated by the fish-specifically high leptin levels induced by the cooperation of insulin and glucagon.


Assuntos
Privação de Alimentos/fisiologia , Carpa Dourada/genética , Insulina/farmacologia , Leptina/genética , Fígado/metabolismo , Animais , Colforsina/farmacologia , Jejum , Comportamento Alimentar/efeitos dos fármacos , Glucagon/farmacologia , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Humanos , Injeções Intraperitoneais , Insulina/administração & dosagem , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like II/farmacologia , Leptina/metabolismo , Fígado/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores para Leptina/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Genes (Basel) ; 10(8)2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398921

RESUMO

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.


Assuntos
Adiposidade/efeitos dos fármacos , Depressores do Apetite/farmacologia , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Ocidental/efeitos adversos , Sobrepeso/prevenção & controle , Proantocianidinas/farmacologia , Tecido Adiposo/metabolismo , Animais , Depressores do Apetite/uso terapêutico , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Leptina/genética , Leptina/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Sobrepeso/tratamento farmacológico , Proantocianidinas/uso terapêutico , Ratos , Vitis/química
13.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443349

RESUMO

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.


Assuntos
Adipocinas/metabolismo , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Adipocinas/genética , Animais , Artrite Reumatoide/patologia , Biomarcadores , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Resistina/genética , Resistina/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Endocrinology ; 160(10): 2367-2387, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265057

RESUMO

Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sex-dependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BL/6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.


Assuntos
Glicemia/metabolismo , Corticosterona/toxicidade , Resistência à Insulina , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adipocinas/genética , Adipocinas/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Insulina/farmacologia , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Fatores Sexuais
15.
PLoS Genet ; 15(6): e1008244, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233501

RESUMO

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.


Assuntos
Adiponectina/genética , Leptina/genética , Lipodistrofia Generalizada Congênita/genética , Osteosclerose/genética , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Densidade Óssea/genética , Modelos Animais de Doenças , Feminino , Glucose/genética , Glucose/metabolismo , Humanos , Insulina/genética , Gordura Intra-Abdominal/metabolismo , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/patologia , Camundongos , Camundongos Knockout , Osteosclerose/etiologia , Osteosclerose/metabolismo , Osteosclerose/patologia , Esqueleto/metabolismo , Esqueleto/patologia , Gordura Subcutânea/metabolismo
16.
Nutrients ; 11(6)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234503

RESUMO

Nutrition in the postnatal period is associated with metabolic programming. One of the presumed underlying mechanisms involves epigenetic modifications (e.g., DNA methylation). Breastfeeding has an unknown impact on DNA methylation at a young age. Within the Maternal Nutrition and Offspring's Epigenome (MANOE) study, we assessed the effect of breastfeeding duration on infant growth and buccal methylation in obesity-related genes (n = 101). A significant difference was found between infant growth and buccal RXRA and LEP methylation at 12 months of breastfeeding. For RXRA CpG2 methylation, a positive association was found with duration of breastfeeding (slope = 0.217; 95% confidence interval (CI) 1.03, 0.330; p < 0.001). For RXRA CpG3 and CpG, mean methylation levels were significantly lower when children were breastfed for 4-6 months compared to non-breastfed children (only CpG3), and those breastfed for 7-9 months, 10-12 months, or 1-3 months. On the other hand, higher LEP CpG3 methylation was observed when mothers breastfed 7-9 months (6.1%) as compared to breastfeeding for 1-3 months (4.3%; p = 0.007) and 10-12 months (4.6%; p = 0.04). In addition, we observed that infant weight was significantly lower when children were breastfed for 10-12 months. Breastfeeding duration was associated with epigenetic variations in RXRA and LEP at 12 months and with infant biometry/growth. Our results support the hypothesis that breastfeeding could induce epigenetic changes in infants.


Assuntos
Aleitamento Materno , Metilação de DNA , Leptina/genética , Metaboloma/genética , Obesidade Pediátrica/genética , Receptor X Retinoide alfa/genética , Adulto , Fatores Etários , Desenvolvimento Infantil , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Fator de Crescimento Insulin-Like II/genética , Obesidade Pediátrica/metabolismo , Obesidade Pediátrica/fisiopatologia , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Ganho de Peso/genética , Adulto Jovem
17.
Acta Biochim Biophys Sin (Shanghai) ; 51(7): 707-714, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31187140

RESUMO

Alteration in cellular energy metabolism plays a critical role in the development and progression of cancer. Leptin is a hormone secreted by adipose tissue. Recent reports have shown that leptin can induce cancer cell proliferation and regulate cell energy metabolism, but the regulatory mechanism is still unclear. Here, we showed that leptin could promote cell proliferation and maintain high adenosine triphosphate levels in HCT116 and MCF-7 cells. The expression levels of carnitine palmitoyl transferase 1A (CPT1A), pyruvate dehydrogenase, succinate dehydrogenase subunit A and mitochondrial respiratory chain-associated proteins NADH dehydrogenase 1 (ND1), NADH:ubiquinone oxidoreductase subunit B8, and mitochondrial transcription factor A (TFAM) were distinctly increased in leptin-treated HCT116 and MCF-7 cells, while fatty acid synthase and lactate dehydrogenase expression were downregulated. Simultaneously, we found that c-Myc and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) protein expression levels were significantly increased. These results indicated that leptin boosted fatty acid ß-oxidation and the tricarboxylic acid cycle, enhanced oxidative phosphorylation (OXPHOS) activity, and inhibited fatty acid synthesis and glycolysis in tumor cells. Gene transfection experiments revealed that leptin could induce the expression of c-Myc. Moreover, the expressions of PGC-1, CPT1A, and TFAM proteins were downregulated in HCT116 cells with low expression of c-Myc, and the expression levels of these proteins were increased in HCT116 cells overexpressing c-Myc. These findings suggest that leptin plays an important role in the regulation of energy metabolism in tumor cells. It may regulate fatty acid oxidation and OXPHOS of tumor cells by regulating the c-Myc/PGC-1 pathway. Targeting metabolic pathways for cancer treatment has been investigated as potential preventive or therapeutic methods. This study has important implications for the clinical therapy of tumor cell metabolism through hormone regulation.


Assuntos
Ácidos Graxos/metabolismo , Leptina/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HEK293 , Humanos , Leptina/genética , Leptina/metabolismo , Células MCF-7 , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução/efeitos dos fármacos
18.
Food Funct ; 10(6): 3696-3705, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31168538

RESUMO

The consumption of diets rich in fat and refined sugars is recognized to be one of the causes of lifestyle disorders, and dietary fibres are being advocated to ameliorate the complications associated with these disorders. In the present study, the effects of two soluble fermentable fibres, viz., gum acacia and inulin on the progression of adiposity, insulin resistance, and the expression of genes related to metabolism were examined in C57BL/6 mice fed a high-fat and sucrose diet for 18 weeks. The feeding of either type of fibre resulted in decrease in body weight, epididymal fat mass, adipocyte size, hyperlipidaemia, hyperglycaemia and hyperinsulinemia. In the fibre-fed groups, the expressions of adiponectin and glucose transporter 4 in the epididymal fat increased significantly, while the expressions of leptin, interleukin 6 and tumor necrosis factor alpha decreased significantly. Moreover, the expressions of genes related to beta-oxidation, viz., carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor gamma co-activator 1ß, and peroxisome proliferator-activated receptor alpha in the liver tissue of the fibre-fed groups enhanced significantly. Furthermore, due to the feeding of either type of fibre, the expressions of zonula occludens 1 and fasting-induced adipose factor in the distal ileum and proglucagon in the colon increased significantly. From the results of the present study, it can be concluded that the beneficial effects of the fibres are mediated due to enhanced energy expenditure, improved intestinal integrity, and reduced inflammation.


Assuntos
Adiposidade , Goma Arábica/metabolismo , Resistência à Insulina , Inulina/metabolismo , Obesidade/tratamento farmacológico , Adiponectina/genética , Adiponectina/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/efeitos adversos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/metabolismo , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia
19.
Breast Cancer Res ; 21(1): 67, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118047

RESUMO

BACKGROUND: Breast cancer is the second leading cause of cancer deaths in the USA. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with high rates of metastasis, tumor recurrence, and resistance to therapeutics. Obesity, defined by a high body mass index (BMI), is an established risk factor for breast cancer. Women with a high BMI have increased incidence and mortality of breast cancer; however, the mechanisms(s) by which obesity promotes tumor progression are not well understood. METHODS: In this study, obesity-altered adipose stem cells (obASCs) were used to evaluate obesity-mediated effects of TNBC. Both in vitro and in vivo analyses of TNBC cell lines were co-cultured with six pooled donors of obASCs (BMI > 30) or ASCs isolated from lean women (lnASCs) (BMI < 25). RESULTS: We found that obASCs promote a pro-metastatic phenotype by upregulating genes associated with epithelial-to-mesenchymal transition and promoting migration in vitro. We confirmed our findings using a TNBC patient-derived xenograft (PDX) model. PDX tumors grown in the presence of obASCS in SCID/beige mice had increased circulating HLA1+ human cells as well as increased numbers of CD44+CD24- cancer stem cells in the peripheral blood. Exposure of the TNBC PDX to obASCs also increased the formation of metastases. The knockdown of leptin expression in obASCs suppressed the pro-metastatic effects of obASCs. CONCLUSIONS: Leptin signaling is a potential mechanism through which obASCs promote metastasis of TNBC in both in vitro and in vivo analyses.


Assuntos
Tecido Adiposo/citologia , Transformação Celular Neoplásica/metabolismo , Leptina/biossíntese , Células-Tronco/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biópsia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Leptina/genética , Camundongos , Obesidade/metabolismo , Neoplasias de Mama Triplo Negativas/etiologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biomed Res Int ; 2019: 2585743, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119158

RESUMO

Purpose: Leptin is a nutritional cytokine encoded by the obesity gene whose concentration in the tumor microenvironment is closely related to the occurrence and progression of cancer. However, previous evidence has suggested that there is no clear relationship between serum leptin concentrations and lung cancer progression. Cancer-associated fibroblasts (CAFs), the most abundant component of the tumor microenvironment in a variety of solid tumors, were recently reported to produce leptin. Therefore, it was inferred that leptin is most likely to affect non-small-cell lung cancer (NSCLC) through an autocrine and paracrine mechanism. In the current study, we investigated the paracrine effect and mechanism of leptin produced by CAFs on NSCLC by establishing a novel in vitro cell coculture system. Methods: A noncontact coculture device was designed and made by 3D printing. CAFs and paired normal lung fibroblasts (NLFs) from 5 patients were successfully isolated and cocultured with two NSCLC cell lines in a coculture system. The background expression of leptin was detected by western blot. The in situ expression of leptin and its receptor (Ob-R) in NSCLC tissues and paired normal lung tissues was analyzed by immunohistochemistry. Furthermore, we downregulated the expression of leptin in CAFs and assessed changes in its promotion on NSCLC cells in the coculture system. Finally, changes in the phosphorylation of ERK1/2 and AKT were examined to investigate the molecular mechanisms responsible for the paracrine promotion of NSCLC cells by leptin. Results: Leptin was overexpressed in nearly all five primary CAF lines compared with its expression in paired NLFs. IHC staining showed that the expression of leptin was high in NSCLC cells, slightly lower in CAF, and negative in normal lung tissue. Ob-R was strongly expressed in NSCLC cells. The ability of A549 and H1299 cells to proliferate and migrate was enhanced by high leptin levels in both the cocultured fibroblasts and the culture medium. Furthermore, western blot assays suggested that the MAPK/ERK1/2 and PI3K/AKT signaling pathways were activated by leptin produced by CAFs, which demonstrated that the functions of paracrine leptin in NSCLC are as those of the serum leptin to other cancers. Conclusion: Leptin produced by CAF promotes proliferation and migration of NSCLC cells probably via PI3K/AKT and MAPK/ERK1/2 signaling pathways in a paracrine manner.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/dietoterapia , Proliferação de Células/efeitos dos fármacos , Leptina/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Leptina/genética , Leptina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Comunicação Parácrina/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Microambiente Tumoral/efeitos dos fármacos
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