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1.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502056

RESUMO

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.


Assuntos
Gordura Intra-Abdominal/metabolismo , Leptina/genética , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Osteoporose/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leptina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Osteoblastos/citologia , Osteoporose/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Peroxissomos/metabolismo , Receptores Purinérgicos P2X5/genética , Receptores Purinérgicos P2X5/metabolismo , Simportadores/genética , Simportadores/metabolismo , Termogênese , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
2.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502119

RESUMO

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.


Assuntos
Metabolismo Energético , Fertilidade/fisiologia , Leptina/metabolismo , Transdução de Sinais , Biomarcadores , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leptina/genética , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360982

RESUMO

Reproductive function depends upon an operational hypothalamo-pituitary-gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.


Assuntos
Síndrome de Kallmann/metabolismo , Animais , Gônadas/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Síndrome de Kallmann/tratamento farmacológico , Síndrome de Kallmann/genética , Leptina/metabolismo , Prolactina/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445677

RESUMO

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.


Assuntos
Adiponectina/metabolismo , Asma/metabolismo , Asma/fisiopatologia , Adipocinas/metabolismo , Adiponectina/fisiologia , Humanos , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
5.
Adipocyte ; 10(1): 408-411, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34402717

RESUMO

Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Resveratrol/administração & dosagem , Tecido Adiposo/citologia , Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , COVID-19/virologia , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/patologia , Efeito Placebo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Resveratrol/farmacologia , SARS-CoV-2/isolamento & purificação
6.
Oxid Med Cell Longev ; 2021: 2207125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457110

RESUMO

Obesity is increasing worldwide in prepubertal children, reducing the age of onset of associated comorbidities, including type 2 diabetes. Sulfur-containing amino acids, methionine, cysteine, and their derivatives play important roles in the transmethylation and transsulfuration pathways. Dysregulation of these pathways leads to alterations in the cellular methylation patterns and an imbalanced redox state. Therefore, we tested the hypothesis that one-carbon metabolism is already dysregulated in prepubertal children with obesity. Peripheral blood was collected from 64 children, and the plasma metabolites from transmethylation and transsulfuration pathways were quantified by HPLC. The cohort was stratified by BMI z-scores and HOMA-IR indices into healthy lean (HL), healthy obese (HO), and unhealthy obese (UHO). Fasting insulin levels were higher in the HO group compared to the HL, while the UHO had the highest. All groups presented normal fasting glycemia. Furthermore, high-density lipoprotein (HDL) was lower while triglycerides and lactate levels were higher in the UHO compared to HO subjects. S-adenosylhomocysteine (SAH) and total homocysteine levels were increased in the HO group compared to HL. Additionally, glutathione metabolism was also altered. Free cystine and oxidized glutathione (GSSG) were increased in the HO as compared to HL subjects. Importantly, the adipocyte secretory function was already compromised at this young age. Elevated circulating leptin and decreased adiponectin levels were observed in the UHO as compared to the HO subjects. Some of these alterations were concomitant with alterations in the DNA methylation patterns in the obese group, independent of the impaired insulin levels. In conclusion, our study informs on novel and important metabolic alterations in the transmethylation and the transsulfuration pathways in the early stages of obesity. Moreover, the altered secretory function of the adipocyte very early in life may be relevant in identifying early metabolic markers of disease that may inform on the increased risk for specific future comorbidities in this population.


Assuntos
Biomarcadores/análise , Metilação de DNA , Estresse Oxidativo , Obesidade Pediátrica/epidemiologia , Adiponectina/genética , Adiponectina/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Oxirredução , Obesidade Pediátrica/genética , Obesidade Pediátrica/metabolismo , Obesidade Pediátrica/patologia , Estados Unidos/epidemiologia
7.
Oxid Med Cell Longev ; 2021: 7385160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457118

RESUMO

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.


Assuntos
Regulação da Expressão Gênica , Janus Quinase 2/metabolismo , Leptina/metabolismo , Obesidade/complicações , Osteoartrite/patologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Janus Quinase 2/genética , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor 4 Toll-Like/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360753

RESUMO

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteína HMGB1/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Interleucina-2/farmacologia , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/patologia , Hiperinsulinismo/patologia , Leucócitos Mononucleares/patologia
9.
Nat Commun ; 12(1): 5175, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462445

RESUMO

Calcitonin receptor (Calcr)-expressing neurons of the nucleus tractus solitarius (NTS; CalcrNTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh-expressing NTS (PrlhNTS) neurons represent a subset of CalcrNTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of PrlhNTS cells to hypothalamic feeding circuits, we determined the ability of PrlhNTS-mediated signals to overcome enforced activation of AgRP neurons. We found that PrlhNTS neuron activation and Prlh overexpression in PrlhNTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance.


Assuntos
Obesidade/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Núcleo Solitário/metabolismo , Animais , Apetite , Dieta , Ingestão de Alimentos , Metabolismo Energético , Feminino , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Melanocortinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Hormônio Liberador de Prolactina/genética , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo
10.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361783

RESUMO

Amber-the fossilized resin of trees-is rich in terpenoids and rosin acids. The physiological effects, such as antipyretic, sedative, and anti-inflammatory, were used in traditional medicine. This study aims to clarify the physiological effects of amber extract on lipid metabolism in mouse 3T3-L1 cells. Mature adipocytes are used to evaluate the effect of amber extract on lipolysis by measuring the triglyceride content, glucose uptake, glycerol release, and lipolysis-related gene expression. Our results show that the amount of triacylglycerol, which is stored in lipid droplets in mature adipocytes, decreases following 96 h of treatment with different concentrations of amber extract. Amber extract treatment also decreases glucose uptake and increases the release of glycerol from the cells. Moreover, amber extract increases the expression of lipolysis-related genes encoding perilipin and hormone-sensitive lipase (HSL) and promotes the activity of HSL (by increasing HSL phosphorylation). Amber extract treatment also regulates the expression of other adipocytokines in mature adipocytes, such as adiponectin and leptin. Overall, our results indicate that amber extract increases the expression of lipolysis-related genes to induce lipolysis in 3T3-L1 cells, highlighting its potential for treating various obesity-related diseases.


Assuntos
Adipócitos/efeitos dos fármacos , Âmbar/farmacologia , Misturas Complexas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Lipólise/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Âmbar/química , Animais , Diferenciação Celular , Misturas Complexas/química , Etanol/química , Glucose/metabolismo , Glicerol/metabolismo , Hipolipemiantes/química , Leptina/genética , Leptina/metabolismo , Gotículas Lipídicas/química , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Camundongos , Perilipina-1/genética , Perilipina-1/metabolismo , Fosforilação/efeitos dos fármacos , Esterol Esterase/genética , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
11.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356668

RESUMO

Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.


Assuntos
Leptina/agonistas , Leptina/antagonistas & inibidores , Leptina/metabolismo , Anticorpos de Domínio Único/farmacologia , Animais , Sítios de Ligação , Humanos , Leptina/química , Peptídeos/química , Peptídeos/genética , Peptídeos/farmacologia , Receptores para Leptina/antagonistas & inibidores , Receptores para Leptina/química , Receptores para Leptina/metabolismo , Anticorpos de Domínio Único/química
12.
Nat Metab ; 3(8): 1071-1090, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34341568

RESUMO

Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic ß-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.


Assuntos
Encéfalo/metabolismo , Células Ependimogliais/metabolismo , Receptores ErbB/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos , Pâncreas/metabolismo , Receptores para Leptina/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Metabolismo Energético , Células Secretoras de Insulina/metabolismo , Fosforilação
13.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299256

RESUMO

To investigate the effect of leptin in childhood ITP, we measured plasma leptin in 39 children with acute ITP, after treatment and in remission, and in 33 healthy age/BMI-matched controls. We also cultured ITP and control peripheral blood mononuclear cells (PBMCs) with recombinant leptin to assess its direct effect on pro/anti-inflammatory cytokine gene expression. A significant increase in leptin was observed in children with active disease compared to controls. A significant inverse correlation of leptin with platelet count was also observed in children with acute ITP. Leptin remained high after treatment with IVIg, whereas steroid treatment lowered leptin below control levels. In remission, leptin was in the control range. Cytokine gene expression was significantly increased in children with acute ITP compared with controls, with highest expression for IFN-γ and IL-10. IVIg/steroid treatment significantly decreased IFN-γ and IL-10 expression. In remission, IFN-γ and IL-10 expression remained low. Addition of leptin to PBMCs isolated from patients in remission resulted in a significant increase in IL-10 gene expression compared to controls. Further experiments with purified T-cells and monocytes identified monocytes as the source of leptin-induced IL-10. We suggest that leptin acts as an active anti-inflammatory agent in childhood ITP by promoting IL-10 secretion by monocytes.


Assuntos
Leptina/análise , Púrpura Trombocitopênica Idiopática/metabolismo , Adolescente , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Criança , Pré-Escolar , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Feminino , Expressão Gênica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Interferon gama/metabolismo , Interleucina-10/metabolismo , Leptina/sangue , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Monócitos/metabolismo , Plasma/química , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/fisiopatologia , Células Th2/imunologia
14.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299261

RESUMO

Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.


Assuntos
Tecido Adiposo/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Adipocinas/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
15.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299350

RESUMO

Leptin is a cytokine that regulates appetite and energy expenditure, where in fishes it is primarily produced in the liver and acts to mobilize carbohydrates. Most fishes have only one leptin receptor (LepR/LepRA1), however, paralogs have recently been documented in a few species. Here we reveal a second leptin receptor (LepRA2) in rainbow trout that is 77% similar to trout LepRA1. Phylogenetic analyses show a salmonid specific genome duplication event as the probable origin of the second LepR in trout. Tissues distributions showed tissue specific expression of these receptors, with lepra1 highest in the ovaries, nearly 50-fold higher than lepra2. Interestingly, lepra2 was most highly expressed in the liver while hepatic lepra1 levels were low. Feed deprivation elicited a decline in plasma leptin, an increase in hepatic lepra2 by one week and remained elevated at two weeks, while liver expression of lepra1 remained low. By contrast, muscle lepra1 mRNA increased at one and two weeks of fasting, while adipose lepra1 was concordantly lower in fasted fish. lepra2 transcript levels were not affected in muscle and fat. These data show lepra1 and lepra2 are differentially expressed across tissues and during feed deprivation, suggesting paralog- and tissue-specific functions for these leptin receptors.


Assuntos
Oncorhynchus mykiss/metabolismo , Receptores para Leptina/metabolismo , Tecido Adiposo/metabolismo , Sequência de Aminoácidos , Animais , Apetite/fisiologia , Metabolismo Energético/fisiologia , Jejum/metabolismo , Proteínas de Peixes/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Músculos/metabolismo , Filogenia , RNA Mensageiro/metabolismo , Alinhamento de Sequência
16.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298894

RESUMO

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Adiponectina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Receptores para Leptina/metabolismo
17.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201760

RESUMO

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPRb, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPRb positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the NTS of Leprb-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPRb positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPRb signaling in the NTS.


Assuntos
Neurônios/metabolismo , Receptores de Droga/metabolismo , Receptores para Leptina/metabolismo , Síndromes da Apneia do Sono/fisiopatologia , Núcleo Solitário/citologia , Animais , Eletromiografia , Leptina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Obesidade/etiologia , Obesidade/fisiopatologia , Sono REM , Núcleo Solitário/metabolismo
18.
Fish Physiol Biochem ; 47(4): 1283-1298, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34236575

RESUMO

The signal mediated by leptin hormone and its receptor is a major regulator of body weight, food intake and metabolism. In mammals and many teleost fish species, leptin has an anorexigenic role and inhibits food intake by influencing the appetite centres in the hypothalamus. However, the regulatory connections between leptin and downstream genes mediating its appetite-regulating effects are still not fully explored in teleost fish. In this study, we used a loss of function leptin receptor zebrafish mutant and real-time quantitative PCR to assess brain expression patterns of several previously identified anorexigenic genes downstream of leptin signal under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-h refeeding). These downstream factors include members of cart genes, crhb and gnrh2, as well as selected genes co-expressed with them based on a zebrafish co-expression database. Here, we found a potential gene expression network (GRN) comprising the abovementioned genes by a stepwise approach of identifying co-expression modules and predicting their upstream regulators. Among the transcription factors (TFs) predicted as potential upstream regulators of this GRN, we found expression pattern of sp3a to be correlated with transcriptional changes of the downstream gene network. Interestingly, the expression and transcriptional activity of Sp3 orthologous gene in mammals have already been implicated to be under the influence of leptin signal. These findings suggest a potentially conserved regulatory connection between leptin and sp3a, which is predicted to act as a transcriptional driver of a downstream gene network in the zebrafish brain.


Assuntos
Encéfalo/metabolismo , Leptina/metabolismo , Peixe-Zebra/genética , Animais , Feminino , Proteínas de Peixes/genética , Expressão Gênica , Redes Reguladoras de Genes , Masculino , Fatores de Transcrição/genética , Transcrição Genética , Peixe-Zebra/metabolismo
19.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208585

RESUMO

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.


Assuntos
Leptina/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Regulação da Temperatura Corporal , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Hipotálamo/metabolismo , Leptina/sangue , Leptina/deficiência , Obesidade/diagnóstico , Obesidade/etiologia , Obesidade/terapia , Termogênese , Resultado do Tratamento
20.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202165

RESUMO

Orthodontic treatment to correct dental malocclusions leads to the formation of pressure zones in the periodontal ligament resulting in a sterile inflammatory reaction, which is mediated by periodontal ligament fibroblasts (PDLF). Leptin levels are elevated in obesity and chronic inflammatory responses. In view of the increasing number of orthodontic patients with these conditions, insights into effects on orthodontic treatment are of distinct clinical relevance. A possible influence of leptin on the expression profile of PDLF during simulated orthodontic mechanical strain, however, has not yet been investigated. In this study, PDLF were exposed to mechanical strain with or without different leptin concentrations. The gene and protein expression of proinflammatory and bone-remodelling factors were analysed with RT-qPCR, Western-blot and ELISA. The functional analysis of PDLF-induced osteoclastogenesis was analysed by TRAP (tartrate-resistant acid phosphatase) staining in coculture with human macrophages. Pressure-induced increase of proinflammatory factors was additionally elevated with leptin treatment. PDLF significantly increased RANKL (receptor activator of NF-kB ligand) expression after compression, while osteoprotegerin was downregulated. An additional leptin effect was demonstrated for RANKL as well as for subsequent osteoclastogenesis in coculture after TRAP staining. Our results suggest that increased leptin concentrations, as present in obese patients, may influence orthodontic tooth movement. In particular, the increased expression of proinflammatory factors and RANKL as well as increased osteoclastogenesis can be assumed to accelerate bone resorption and thus the velocity of orthodontic tooth movement in the orthodontic treatment of obese patients.


Assuntos
Fibroblastos/fisiologia , Leptina/metabolismo , Fenômenos Mecânicos , Ligamento Periodontal/citologia , Ligamento Periodontal/metabolismo , Biomarcadores , Remodelação Óssea , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Osteoclastos/metabolismo , Osteogênese , Receptores para Leptina/metabolismo
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