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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 ; 723: 143986, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323309

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Accumulating evidence shows that microRNAs play important roles in diabetic kidney. However, the potential role of MicroRNA-544 (miR-544) in DN remains unclear. In this study, we explored the role of miR-544 on inflammation and fibrosis in diabetic kidney using db/db mice. Renal expression of miR-544 was decreased in mice, companied by increased the expression of FASN. The dual luciferase assay confirmed FASN as a direct target of miR-544. Over-expression of miR-544 significantly ameliorated renal injury, mesangial matrix and renal fibrosis. In addition, over-expression of miR-544 significantly attenuated inflammatory cells infiltration and IL-1, IL-6, TNF- and iNOS production in DN. Furthermore, miR-544 over-expression inhibited the activation of NF-kB signal pathway in DN. In conclusion, our finding demonstrated that miR-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN, suggesting that miR-544 might have therapeutic potential for the treatment of DN.


Assuntos
Citocinas/metabolismo , Nefropatias Diabéticas/genética , Ácido Graxo Sintase Tipo I/genética , MicroRNAs/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Regiões 3' não Traduzidas , Animais , Nefropatias Diabéticas/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Células HEK293 , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Camundongos , NF-kappa B/metabolismo , Receptores para Leptina/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
3.
Artif Cells Nanomed Biotechnol ; 47(1): 3664-3670, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31841394

RESUMO

This study aimed to explore the role of obestatin R gene-related protein (OB-RGRP) in autocrine signal transduction of adipocytes. Primary rat adipocytes were isolated and verified by microscopic observation and oil red O staining. OB-RGRP expression vector and OB-RGRP siRNA (si-OB-RGRP) were constructed and transfected into adipocytes. Adipocytes were then divided into five groups: (1) Control; (2) Vector (empty expression vector); (3) OB-RGRP (OB-RGRP expression vector); (4) si-OB-RGRP NC (si-OB-RGRP negative control); (5) si-OB-RGRP. mRNA and protein levels of OB-RGRP, JAK2, phosphorylated JAK2 (p-JAK2), STAT3 and phosphorylated STAT3 (p-STAT3) were examined using RT-PCR and western blot, respectively. Results showed that mRNA and protein levels of OB-RGRP in the Vector and si-OB-RGRP NC groups were similar to those in the Control group. Their levels in the si-OB-RGRP and OB-RGRP groups were significantly down-regulated and up-regulated (p < .05), respectively, in comparison with the control cells. There was no significant difference in the mRNA and protein levels of JAK2 and STAT3 among various groups. Moreover, the si-OB-RGRP NC and Vector groups induced similar ratios of p-JAK2 to JAK2 (p-JAK2/JAK2) and p-STAT3 to STAT3 (p-STAT3/STAT3) to the Control group. However, these two ratios in the si-OB-RGRP and OB-RGRP groups were significantly reduced and elevated (p < .05), respectively, in comparison with the Control group. These results suggested that OB-RGRP overexpression enhanced the levels of p-JAK2 and p-STAT3 while OB-RGRP silencing lowered their levels. In conclusion, OB-RGRP regulated the phosphorylation of JAK2 and STAT3 in primary rat adipocytes.


Assuntos
Adipócitos/metabolismo , Janus Quinase 2/metabolismo , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Adipócitos/citologia , Animais , Comunicação Autócrina , Inativação Gênica , Fosforilação , Ratos , Receptores para Leptina/deficiência , Receptores para Leptina/genética
4.
Crit Rev Eukaryot Gene Expr ; 29(2): 171-176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679272

RESUMO

Previous studies examining the association of leptin receptor (LEPR) Gln223Arg polymorphism with obstructive sleep apnea-hypopnea syndrome (OSAHS) risk have yielded controversial outcomes. We aimed to clarify whether LEPR Gln223Arg polymorphism was critically involved in the development of OSAHS. We thoroughly searched PubMed as well as CNKI datasets for collection of relevant studies, followed by analysis of odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Of the seven case-control studies we enrolled, there was insignificant correlation of the LEPR Gln223Arg polymorphism with OSAHS risk. However, subgroup analysis by Newcastle-Ottawa scale (NOS) scores revealed that, LEPR Gln223Arg polymorphism was significantly related to OSAHS risk in high-quality studies. In addition, we found no publication bias. Our findings suggest that LEPR Gln223Arg polymorphism might contribute to the risk of OSAHS. Well-designed studies with more subjects are needed for further validation of these results.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptores para Leptina/genética , Apneia Obstrutiva do Sono/genética , Estudos de Casos e Controles , Genótipo , Humanos , Razão de Chances
5.
Nat Med ; 25(11): 1761-1771, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700184

RESUMO

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.


Assuntos
Aterosclerose/terapia , Doenças Cardiovasculares/terapia , Células-Tronco Hematopoéticas/metabolismo , Inflamação/terapia , Condicionamento Físico Animal , Tecido Adiposo/metabolismo , Animais , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Exercício Físico/fisiologia , Hematopoese/genética , Hematopoese/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Inflamação/fisiopatologia , Leucócitos/metabolismo , Leucocitose/fisiopatologia , Leucocitose/terapia , Camundongos , Receptores para Leptina/genética , Comportamento Sedentário , Transcriptoma/genética
6.
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
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 334-338, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631599

RESUMO

Objective: To study the mechanism of renal injury in Lepr db/ db mice with the leptin receptor homozygous deficiency. Methods: Ten male of 28-week-old Lepr db/+ mice with leptin receptor heterozygous deficiency were selected as control group and ten male Lepr db/ db mice with leptin receptor homozygous deficiency were used in this study. After fasting for 8 hours, the body mass, fasting blood glucose (FBG) and glycosylated hemoglobulin (HbA1c) of the mice were measured. Blood of the mice was obtained from femoral artery before euthanasia. Serum creatinine (CRE), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH) and malonaldehyde (MDA) were detected by corresponding kits, and serum interleukin-1ß (IL-1ß), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA) method. The kidney was taken for pathological observation. The expression levels of nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) in renal were analyzed by Western blot. The mitochondria of renal was isolated by the corresponding kit. Meanwhile, the expression level of lipoic acid synthase (LIAS) in renal mitochondria was measured by Western blot. Results: The body mass, FPG, HbA1c, CRE and BUN levels of the Lepr db/ db mice were significantly increased in comparison with the Lepr db/+ mice ( P<0.05). Compared with the Lepr db/+ mice, the Lepr db/ db mice renal exhibited glomerular hypertrophy, thickened basement membrane and capillary wall, the mesangial matrix expansion and mesangial cell hyperplasia. Compared with the Lepr db/+ mice, the serum level of GSH in the Lepr db/ db mice was decreased significantly ( P<0.05). The levels of MDA and concentrations of MCP-1, IL-1ß and TNF-α in serum of the Lepr db/ db mice were higher than those of the Lepr db/+ mice ( P<0.05). Compared with the Lepr db/+ mice, the expression of LIAS and Nrf2 protein in the Lepr db/ db mice renal were decreased ( P<0.05), while the expression of NF-κB protein was increased ( P<0.05). Conclusion: LIAS, Nrf2 and NF-κB might play significant roles through regulation of oxidative stress and inflammation in the renal injury of Lepr db/ db mice.


Assuntos
Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptores para Leptina/genética , Sulfurtransferases/metabolismo , Animais , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo
8.
Nutrients ; 11(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546853

RESUMO

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated.


Assuntos
Bulimia , Dieta Hiperlipídica , Etanol/toxicidade , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Adiposidade , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Hipocampo/metabolismo , Aprendizagem/fisiologia , Leptina/sangue , Masculino , Camundongos , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Ganho de Peso
9.
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
10.
Nat Commun ; 10(1): 3168, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320650

RESUMO

Multipotent mesenchymal stromal cells (MSCs) are required for skeletal formation, maintenance, and repair throughout life; however, current models posit that postnatally arising long-lived adult MSCs replace transient embryonic progenitor populations. We previously reported exclusive expression and function of the embryonic patterning transcription factor, Hoxa11, in adult skeletal progenitor-enriched MSCs. Here, using a newly generated Hoxa11-CreERT2 lineage-tracing system, we show Hoxa11-lineage marked cells give rise to all skeletal lineages throughout the life of the animal and persist as MSCs. Hoxa11 lineage-positive cells give rise to previously described progenitor-enriched MSC populations marked by LepR-Cre and Osx-CreER, placing them upstream of these populations. Our studies establish that Hox-expressing cells are skeletal stem cells that arise from the earliest stages of skeletal development and self-renew throughout the life of the animal.


Assuntos
Adipócitos/citologia , Condrócitos/citologia , Proteínas de Homeodomínio/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Animais , Regeneração Óssea/genética , Osso e Ossos/citologia , Osso e Ossos/embriologia , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Receptores para Leptina/genética , Fator de Transcrição Sp7/genética
11.
Obes Facts ; 12(4): 460-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31357197

RESUMO

BACKGROUND AND OBJECTIVE: Hyperleptinemia is supposed to play a causal role in the development of obesity-associated hypertension, possibly via increased sympathetic tone. Hence patients with congenital leptin deficiency should be hypotensive and their low blood pressure should increase under leptin substitution. SUBJECTS AND METHODS: To test this assumption, we examined ambulatory blood pressure, resting heart rate, Schellong test results, cold pressor test results, heart rate variability, catecholamine metabolites, and aldosterone levels in 6 patients with congenital leptin deficiency before as well as 2-7 days and 7-14 months after the start of leptin substitution. Ambulatory blood pressure was also examined in 3 patients with biallelic disease-causing variants in the leptin receptor gene. RESULTS: Contrary to our expectations, even before leptin substitution, 1 patient with biallelic leptin receptor gene variants and 4 patients with leptin deficiency had been suffering from hypertension. Short-term substitution with leptin increased blood pressure further in 3 out of 4 patients (from 127.0 ± 11.7 to 133.8 ± 10.6 mm Hg), concomitant with an increase in resting heart rate as well as in heart rate during the Schellong test in all patients (from 87.6 ± 7.7 to 99.9 ± 11.0 bpm, p = 0.031, and from 102.9 ± 13.5 to 115.6 ± 11.3 bpm, p = 0.031, respectively). Furthermore, the systolic blood pressure response during the cold pressor test increased in 4 out of 6 patients. Unexpectedly, catecholamine metabolites and aldosterone levels did not increase. After long-term leptin substitution and weight loss, the resting heart rate decreased in 4 out of 6 patients compared to baseline, and in all patients below the heart rate seen immediately after the start of therapy (from 99.9 ± 11.0 to 81.7 ± 5.4 bpm; p = 0.031). CONCLUSIONS: These results show that obesity-associated hypertension does not depend on the presence of leptin. However, short-term leptin substitution can increase the blood pressure and heart rate in obese humans with leptin deficiency, indicating that leptin plays at least an additive role in obesity-associated hypertension. The mechanisms behind this are not clear but might include an increase in regional sympathetic tone.


Assuntos
Hipertensão/etiologia , Leptina/fisiologia , Obesidade/complicações , Obesidade/genética , Receptores para Leptina/genética , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Criança , Estudos de Coortes , Feminino , Frequência Cardíaca/efeitos dos fármacos , Terapia de Reposição Hormonal , Humanos , Hipertensão/sangue , Hipertensão/genética , Leptina/análogos & derivados , Leptina/deficiência , Leptina/uso terapêutico , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/fisiopatologia , Obesidade/sangue , Obesidade/fisiopatologia , Perda de Peso/fisiologia , Adulto Jovem
12.
Curr Med Sci ; 39(4): 609-614, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31346998

RESUMO

The effects of metformin treatment on soluble leptin receptor (sOB-R) levels in women with polycystic ovary syndrome (PCOS) were investigated. This prospective and open-label study was conducted by the Department of Obstetrics & Gynecology at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, China. Fifty-five women with PCOS and insulin resistance (IR) were treated with metformin for 6 months. According to body mass index (BMI), the patients were divided into two groups: lean PCOS group (BMI <23 kg/m2, n=34) and overweight or obese PCOS group (BMI ≥23 kg/m2, n=21). Before and after treatment, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), insulin and sOB-R levels were determined. Thirty-one BMI-matched ovulatory women served as controls. The results showed: (1) The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), androgen levels and hirsutism scores were higher, and sOB-R levels were lower in PCOS groups than in control group. A subgroup analysis of lean and overweight or obese PCOS patients revealed there was significant difference in sOB-R level between lean PCOS group and overweight or obese PCOS group. There were no significant differences in anthropometric parameters between lean PCOS patients and BMI-matched controls. However, sOB-R level was significantly lower in lean PCOS women than in controls. (2) There was no correlation between sOB-R level and BMI, waist and hip circumference, total testosterone, androstendione, DHEAS, LH or hirsutism scores in PCOS patients, but there was a significant negative correlation between sOB-R and HOMA-IR. (3) After treatment with metformin for 6 months, serum insulin levels decreased, and sOB-R levels increased significantly (P<0.01). It was suggested that considering low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance. It is likely that reduction of hyperinsulinemia produced by metformin effectively improves the sOB-R levels in PCOS.


Assuntos
Metformina/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Receptores para Leptina/genética , Adulto , Androstenodiona/sangue , Índice de Massa Corporal , Sulfato de Desidroepiandrosterona/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Insulina/sangue , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Testosterona/sangue
13.
J Diabetes Res ; 2019: 2714049, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192261

RESUMO

Most peripheral serotonin (5-hydroxytryptamine (5HT)) is synthetized in the gut with platelets being its main circulating reservoir. 5HT is acting as a hormone in key organs to regulate glucose and lipid metabolism. However, the relation between platelet 5HT levels and traits related to glucose homeostasis and lipid metabolism in humans remains poorly explored. The objectives of this study were (a) to assess the association between platelet 5HT levels and plasma concentration of nonesterified fatty acids (NEFAs) and some adipokines including leptin and its soluble leptin receptor (sOb-R), (b) to assess the association between platelet 5HT levels and anthropometric traits and indexes of insulin secretion/sensitivity derived from oral glucose tolerance test (OGTT), and (c) to evaluate changes in platelet 5HT levels in response to OGTT. In a cross-sectional study, 59 normoglycemic women underwent a standard 2-hour OGTT. Plasma leptin, sOb-R, total and high molecular weight adiponectin, TNFα, and MCP1 were determined by immunoassays. Platelet 5HT levels and NEFAs were measured before and after OGTT. The free leptin index was calculated from leptin and sOb-R measurements. Insulin sensitivity indexes derived from OGTT (HOMA-S and Matsuda ISICOMP) and plasma NEFAs (Adipose-IR, Revised QUICKI) were also calculated. Our data show that among metabolic traits, platelet 5HT levels were associated with plasma sOb-R (r = 0.39, p = 0.003, corrected p = 0.018). Platelet 5HT levels were reduced in response to OGTT (779 ± 237 vs.731 ± 217 ng/109 platelets, p = 0.005). In conclusion, platelet 5HT levels are positively associated with plasma sOb-R concentrations and reduced in response to glucose intake possibly indicating a role of peripheral 5HT in leptin-mediated appetite regulation.


Assuntos
Adipocinas/sangue , Plaquetas/química , Receptores para Leptina/sangue , Serotonina/sangue , Adiponectina/sangue , Adulto , Antropometria , Glicemia/análise , Índice de Massa Corporal , Quimiocina CCL2/sangue , Chile , Estudos Transversais , Ácidos Graxos não Esterificados/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Resistência à Insulina , Leptina/sangue , Metabolismo dos Lipídeos , Lipídeos/sangue , Receptores para Leptina/genética , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
14.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234537

RESUMO

Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA on dyslipidemia and MetSyn remains unclear. To address this question, leptin receptor knock out (KO)-db/db mice were randomly assigned to three different groups: A normal AIN76-A diet (CON), a Western diet (WD) and a Western diet with 0.1% NDGA and an LPL inhibitor, (WD+NDGA). All mice were fed for 12 weeks. The LPL inhibition by NDGA was confirmed by measuring the systemic LPL mass and adipose LPL gene expression. We investigated whether the LPL inhibition by NDGA alters the metabolic phenotypes. NDGA led to hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. More strikingly, the supplementation of NDGA increased the percentage of high density lipoprotein (HDL)small (HDL3a+3b+3c) and decreased the percentage of HDLlarge (HDL2a+2b) compared to the WD group, which indicates that LPL inhibition modulates HDL subclasses. was NDGA increased adipose inflammation but had no impact on hepatic stress signals. Taken together, these findings demonstrated that LPL inhibition by NDGA aggravates metabolic parameters and alters HDL particle size.


Assuntos
Lipase Lipoproteica/antagonistas & inibidores , Lipoproteínas HDL/metabolismo , Masoprocol/farmacologia , Animais , Dieta Ocidental , Masculino , Camundongos , Camundongos Knockout , Tamanho da Partícula , Receptores para Leptina/genética
15.
BMC Cancer ; 19(1): 443, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088516

RESUMO

BACKGROUND: The progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors. METHODS: We performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness. RESULTS: Our results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the "high risk" prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females. CONCLUSIONS: For the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects' trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.


Assuntos
Mutação em Linhagem Germinativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequenciamento Completo do Exoma/métodos , Aptidão Cardiorrespiratória , Criança , Pré-Escolar , Conectina/genética , Feminino , Estudos de Associação Genética , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Receptores para Leptina/genética , Sobreviventes
16.
Mol Cell Biochem ; 458(1-2): 207-217, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077012

RESUMO

Leptin induces ovarian cancer cell invasion via overexpression of MMP7, MMP9, and upA. In addition, the key role of ERα in leptin-increased cell growth was indicated. However, the influence of ER on leptin-mediated cell invasion remains still unknown. The present study was designed to evaluate the E2-independent effect of ERα/ß on leptin-mediated cell invasion and cell proliferation in ovarian cancer. We utilized SKOV3 cancer (expressing OB-Rb and ERα/ß, insensitive to estrogen) and OVCAR3 (expressing OB-Rb) cell lines to show the involvement of ER in leptin-mediated effects in an E2-independent manner. MTT, BrdU, and BD matrigel invasion assays were applied to analyze cell growth, proliferation, and invasion. The siRNA approach was used to confirm the role of ERα/ß in leptin effects. Moreover, western blotting and Real-time PCR were employed to detect the OB-Rb, ER, MMP9/7, and upA proteins and mRNAs. Leptin, in the absence of E2, increased ERα expression in SKOV3 cells, which was attenuated using knockdown of OB-Rb gene by siRNA. The effect of leptin on the cell growth was promoted in the presence of PPT, but not in the presence of DNP and E2, which was lost when OB-Rb siRNA was transfected. Furthermore, ERα gene silencing and/or pre-incubation with ER antagonist (ICI 182,780, 10 nM) significantly reduced cell invasion and MMP9 expression stimulated by leptin. In conclusion, our findings demonstrated that ERα, but not ERß, is involved in leptin-induced ovarian cancer in an E2-independent manner, providing new evidence for cancer progression in obesity-associated ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Receptor alfa de Estrogênio/metabolismo , Leptina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores para Leptina/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Leptina/genética , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptores para Leptina/genética
17.
Arch Oral Biol ; 103: 26-32, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128439

RESUMO

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a complex disease influenced by genes and the environment. Periodontitis a demonstrated risk factor of T2DM. Previous studies related to gene-environment interactions on the risk of T2DM mainly focused on gene-obesity interactions. However, the impact of gene-periodontitis interaction on the risk of T2DM has not yet been investigated. This study aimed to investigate gene-environment interactions among moderate/severe periodontitis, polymorphisms of adiponectin (ADIPOQ)-rs1501299, and leptin receptor (LEPR)-rs1137100 on T2DM risk in Chinese subjects. DESIGN: A case-control study was conducted in 239 Chinese participants from Beijing Hypertension Association Institute (BHAL). After full-mouth periodontal examinations, the participants underwent bilateral buccal swabs for DNA testing. ADIPOQ-rs1501299 and LEPR-rs1137100 were used for genotyping. Generalised multifactor dimensionality reduction (GMDR) and logistic regression were used to examine the interactions among single nucleotide polymorphisms (SNPs) and moderate/severe periodontitis on the risk of T2DM. RESULTS: The risk of T2DM was higher in moderate/severe periodontitis [adjusted odds ratio (AOR) = 3.67, 95% confidence interval (95%CI): 1.26-10.71] in ADIPOQ-rs1501299 GG genotype (AOR = 3.42, 95%CI: 1.81-6.46) and LEPR-rs1137100 GG genotype (AOR = 3.16, 95%CI: 1.56-6.39). The GMDR model indicated that there was a significant three-factor model (p = 0.001) involving rs1501299, rs1137100, and moderate/severe periodontitis, demonstrating a potential gene-environment interaction among periodontitis, polymorphisms of rs1501299, and rs1137100 influencing the risk of T2DM. Moderate/severe periodontitis patients with rs1501299-GG and rs1137100-GG have the highest T2DM risk after adjusting for age, gender, BMI, WHR, smoking status, alcohol consumption, economic status, and hypertension (AOR = 20.39, 95%CI: 2.64-157.26). CONCLUSIONS: Interactions among moderate/severe periodontitis, rs1501299-GG, and rs1137100-GG were associated with an increased risk of T2DM. This study may provide a new insight into the effect of gene-environment interactions on T2DM.


Assuntos
Adiponectina/genética , Diabetes Mellitus Tipo 2/genética , Interação Gene-Ambiente , Periodontite/epidemiologia , Periodontite/genética , Receptores para Leptina/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141984

RESUMO

Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity.


Assuntos
Carcinogênese/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Neoplasias Gástricas/etiologia , Animais , Carcinogênese/genética , Humanos , Leptina/genética , Obesidade/complicações , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
19.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1642-1650, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951821

RESUMO

BACKGROUND: Allergic rhinitis is characterized by a remodeling of nasal epithelium. Since the Notch and TGF-ß signaling pathways are known to be involved in cell differentiation and remodeling processes and leptin adipokine has already been identified as a marker for homeostasis in human bronchial and nasal epithelial cells of asthmatics, roles played by these pathways have been investigated for chronic allergic rhinitis. METHODS: The leptin/leptin receptor expression has been investigated in a study with 40 biopsies from allergic (AR, n = 18) and non-allergic (C, n = 22) inferior turbinates, using immunohistochemistry, immunofluorescence staining and RT-PCR. In addition, extracts from in vitro samples prepared from primary cells of inferior turbinates as well as in vitro cultured human nasal epithelial RPMI 2650 cells (ATCC-CCL-30) were also tested for leptin expression and activation of the Notch-1 pathway. RESULTS: With regards to AR, in vivo expression levels of both leptin and its receptor significantly decreased in comparison to C. Furthermore, leptin receptor mRNA was significantly reduced in AR as compared to C. Immunofluorescence showed an apparent co-expression of leptin receptor with Notch-1, which was not seen with TGF-ß. In vitro, in primary turbinate epithelial cells, the expression of leptin receptor and Notch-1 significantly decreased in AR as compared to C. Moreover, in RPMI 2650 cells, leptin receptor expression was shown to be induced by Notch-1 ligand signaling. CONCLUSION: Thus, both the leptin and Notch-1 pathways appear to represent markers for epithelial homeostasis in allergic rhinitis.


Assuntos
Leptina/genética , Mucosa Nasal/metabolismo , Receptor Notch1/genética , Receptores para Leptina/genética , Rinite Alérgica/genética , Adulto , Biópsia , Estudos de Casos e Controles , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Notch1/metabolismo , Receptores para Leptina/metabolismo , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Conchas Nasais/metabolismo , Conchas Nasais/patologia
20.
Biomedica ; 39(1): 205-211, 2019 03 31.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31021558

RESUMO

INTRODUCTION: Obesity and colorectal cancer could be linked by adipocytokines, which are proteins associated with cell proliferation. High levels of the adipocytokine leptin promote the development of colorectal cancer through its receptor. OBJECTIVE: To determine the association between c.326A>G and c.668A>G LEPR gene polymorphisms and colorectal cancer. MATERIALS AND METHODS: DNA was extracted from the peripheral blood of 147 patients with sporadic colorectal cancer and 134 healthy people. Genotypes were obtained by PCRRFLP and the association was determined by the odds ratio (OR) test using the SPSS™, version 10.0, program. Haplotype frequencies and linkage disequilibrium were estimated by the Arlequin, version 3.5, software. RESULTS: Both polymorphisms were in Hardy-Weinberg equilibrium. Only the c.326A>G heterozygous genotype revealed an increased risk for colorectal cancer development (OR=1.81, 95% CI=1.04-3.16, p=0.04). The AG haplotype showed a significant association with colorectal cancer (OR=0.58, 95% CI=0.35-0.96, p<0.03). Linkage disequilibrium between the variants was only evident for the patients group (r2=0.36). CONCLUSION: Our results suggest that AG individuals heterozygous for the c.326A>G LEPR variant have a higher risk of colorectal cancer development whereas the AG haplotype (c.326A/c.668G) has a protective effect in the Mexican population.


Assuntos
Neoplasias Colorretais/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Receptores para Leptina/genética , Adulto , Idoso , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Adulto Jovem
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