Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.311
Filtrar
1.
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
2.
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
3.
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
4.
J Biochem Mol Toxicol ; 35(9): e22840, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227185

RESUMO

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Receptor de Insulina/metabolismo , Receptores de LDL/metabolismo , Aterosclerose/história , Diabetes Mellitus/história , História do Século XX , História do Século XXI , Humanos , Insulina/história , Insulina/metabolismo , Síndrome Metabólica/história , Obesidade/história , Receptor de Insulina/história , Receptores de LDL/história , Receptores para Leptina/metabolismo
5.
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
6.
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
7.
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
8.
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
9.
Mol Biol (Mosk) ; 55(3): 510-518, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34097685

RESUMO

The hormone leptin is produced in adipocytes of white adipose tissue and crosses the blood-brain barrier. Leptin receptors are present in the brain regions that are involved in higher cognitive functions. In particular, leptin directly influences the glutamate receptor trafficking in CA3 → CA1 synapses to increase the phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) level, which is controlled by phosphoinositide 3-kinase (PI3K). It is well recognized that glutamate receptor trafficking involves at least some components of the insulin signaling cascade. However, the effects of leptin and insulin hormones differ at the cell and behavioral levels and often oppose each other. The domain organization of synaptic proteins was analyzed for CA1 field neurons. A molecular mechanism of leptin effects in the hippocampus was assumed to involve a cross-talk of the molecular pathways of the leptin receptors and NMDA-type glutamate receptors. Non-receptor protein kinases of the Src subfamily and, in particular, kinase Fyn are part of glutamate receptor macrocomplexes and are involved in regulating the efficiency of synaptic transmission. Fyn was assumed to utilize its SH2 domain to interact with leptin receptors directly or through other proteins and contribute to leptin signaling through the PI3K signaling pathway. The hypothesis explains experimental findings and sheds further light on the fine tuning of hormone-dependent modulation of hippocampal synaptic processes.


Assuntos
Ácido Glutâmico , Receptores para Leptina , Hipocampo/metabolismo , Leptina/genética , Leptina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores de N-Metil-D-Aspartato , Sinapses/metabolismo
10.
Commun Biol ; 4(1): 658, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079065

RESUMO

It has not been well studied which cells and related mechanisms contribute to endochondral ossification. Here, we fate mapped the leptin receptor-expressing (LepR+) mesenchymal stem cells (MSCs) in different embryonic and adult extremities using Lepr-cre; tdTomato mice and investigated the underling mechanism using Lepr-cre; Ppp2r1afl/fl mice. Tomato+ cells appear in the primary and secondary ossification centers and express the hypertrophic markers. Ppp2r1a deletion in LepR+ MSCs reduces the expression of Runx2, Osterix, alkaline phosphatase, collagen X, and MMP13, but increases that of the mature adipocyte marker perilipin, thereby reducing trabecular bone density and enhancing fat content. Mechanistically, PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively. Our data identify LepR+ MSC as the cell origin of endochondral ossification during embryonic and postnatal bone growth and suggest that PP2A is a therapeutic target in the treatment of dysregulated bone formation.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Proteína Fosfatase 2/metabolismo , Receptores para Leptina/metabolismo , Adipogenia , Animais , Densidade Óssea , Osso e Ossos/citologia , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Diferenciação Celular , Proliferação de Células , Condrogênese , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Fosforilação , Gravidez , Proteína Fosfatase 2/deficiência , Proteína Fosfatase 2/genética , Fatores de Transcrição/metabolismo
11.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066779

RESUMO

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.


Assuntos
Barreira Hematoencefálica/metabolismo , Leptina/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Animais , Sítios de Ligação , Composição Corporal , Peso Corporal , Células CHO , Plexo Corióideo/metabolismo , Cricetulus , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Luciferases/metabolismo , Masculino , Modelos Biológicos , Fosforilação , Transporte Proteico , Receptores para Leptina/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Suínos
12.
J Endocrinol ; 249(3): 239-251, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33969825

RESUMO

Leptin is a hormone required for the regulation of body weight in adult animals. However, during the postnatal period, leptin is mostly involved in developmental processes. Because the precise moment at which leptin starts to exert its metabolic effects is not well characterized, our objective was to identify the approximate onset of leptin effects on the regulation of energy balance. We observed that male Lepob/ob mice started to exhibit increased body fat mass from postnatal day 13 (P13), whereas in females, the increase in adiposity began on P20. Daily leptin injections from P10 to P22 did not reduce the weight gain of WT mice. However, an acute leptin injection induced an anorexigenic response in 10-day-old C57BL/6 mice but not in 7-day-old mice. An age-dependent increase in the number of leptin receptor-expressing neurons and leptin-induced pSTAT3 cells was observed in the hypothalamus of P7, P10 and P16 mice. Leptin deficiency started to modulate the hypothalamic expression of transcripts involved in the regulation of metabolism between P7 and P12. Additionally, fasting-induced hypothalamic responses were prevented by leptin replacement in 10-day-old mice. Finally, 12-day-old males and females showed similar developmental timing of axonal projections of arcuate nucleus neurons in both WT and Lepob/ob mice. In summary, we provided a detailed characterization of the onset of leptin's effects on the regulation of energy balance. These findings contribute to the understanding of leptin functions during development.


Assuntos
Composição Corporal/efeitos dos fármacos , Metabolismo Energético/fisiologia , Leptina/metabolismo , Leptina/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Animais Lactentes , Composição Corporal/fisiologia , Peso Corporal , Feminino , Desenvolvimento Fetal , Privação de Alimentos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo/metabolismo , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
13.
J Cell Mol Med ; 25(12): 5799-5810, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33988300

RESUMO

Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes from a GD patient set (GD vs healthy control) and a TAO patient set (TAO vs GD). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and receiver operating characteristic (ROC) curve analyses identified the leptin receptor (LEPR) gene as the key IRG in TAO immunopathogenesis. Gene set enrichment analysis (GSEA) suggested enrichment of the antigen presentation pathway in TAO patients with higher LEPR. Increased LEPR expression was validated in TAO orbital tissues, and weighted gene co-expression network analysis (WGCNA) showed that cell adhesion processes were positively correlated with LEPR. Our study revealed that LEPR is a key gene in TAO immunopathogenesis and plays different roles in thyrocytes and orbital tissues. Our findings provide new insights into diagnostic and therapeutic biomarkers for TAO.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Doença de Graves/complicações , Oftalmopatia de Graves/patologia , Receptores para Leptina/metabolismo , Estudos de Casos e Controles , Doença de Graves/imunologia , Doença de Graves/patologia , Oftalmopatia de Graves/etiologia , Oftalmopatia de Graves/metabolismo , Humanos , Curva ROC , Receptores para Leptina/genética
14.
Elife ; 102021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34018926

RESUMO

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing translating ribosome affinity purification with RNA-sequencing (TRAP-seq) data with single-nucleus RNA-sequencing (snRNA-seq) data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of six major genetically and anatomically differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.


Assuntos
Família Multigênica , Neurônios/fisiologia , Transcriptoma , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Genótipo , Ácido Glutâmico/metabolismo , Macaca mulatta , Camundongos Transgênicos , Neurônios/metabolismo , Fenótipo , RNA-Seq , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Especificidade da Espécie , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo
15.
Nat Commun ; 12(1): 2662, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976218

RESUMO

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation.


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hiperglicemia/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/sangue , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Infusões Intraventriculares , Leptina/administração & dosagem , Masculino , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacos
16.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799880

RESUMO

Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.


Assuntos
Carcinogênese/metabolismo , Leptina/metabolismo , Neoplasias/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Adipócitos/metabolismo , Animais , Carcinogênese/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Obesidade/genética , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Microambiente Tumoral/genética
17.
Nutr Metab Cardiovasc Dis ; 31(5): 1635-1644, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812737

RESUMO

BACKGROUND AND AIM: Our previous study found carotid baroreceptor stimulation (CBS) reduces body weight and white adipose tissue (WAT) weight, restores abnormal secretion of adipocytokines and inflammation factors, decreases systolic blood pressure (SBP) by inhibiting activation of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in obese rats. In this study, we explore effects of CBS on aortic remodeling in obese rats. METHODS AND RESULTS: Rats were fed high-fat diet (HFD) for 16 weeks to induce obesity and underwent either CBS device implantation and stimulation or sham operation at 8 weeks. BP and body weight were measured weekly. RAS activity of WAT, histological, biochemical and functional profiles of aortas were detected after 16 weeks. CBS effectively decreased BP in obese rats, downregulated mRNA expression of angiotensinogen (AGT) and renin in WAT, concentrations of AGT, renin, angiotensin II (Ang II), protein levels of Ang II receptor 1 (AT1R) and Ang II receptor 2 (AT2R) in WAT were declined. CBS inhibited reactive oxygen species (ROS) generation, inflammatory response and endoplasmic reticulum (ER) stress in aortas of obese rats, restrained vascular wall thickening and vascular smooth muscle cells (VSMCs) phenotypic switching, increased nitric oxide (NO) synthesis, promoted endothelium-dependent vasodilatation by decreasing protein expression of AT1R and leptin receptor (LepR), increasing protein expression of adiponectin receptor 1 (AdipoR1) in aortic VSMCs. CONCLUSION: CBS reduced BP and reversed aortic remodeling in obese rats, the underlying mechanism might be related to the suppressed SNS activity, restored adipocytokine secretion and restrained RAS activity of WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Terapia por Estimulação Elétrica , Músculo Liso Vascular/patologia , Obesidade/terapia , Pressorreceptores/fisiopatologia , Sistema Renina-Angiotensina , Remodelação Vascular , Adipocinas/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Pressão Arterial , Modelos Animais de Doenças , Terapia por Estimulação Elétrica/instrumentação , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Neuroestimuladores Implantáveis , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Adiponectina , Receptores para Leptina/metabolismo , Vasodilatação
18.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925454

RESUMO

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.


Assuntos
Retardo do Crescimento Fetal/etiologia , Leptina/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Feminino , Retardo do Crescimento Fetal/metabolismo , Humanos , Leptina/sangue , Leptina/fisiologia , Placenta/metabolismo , Gravidez , Receptores para Leptina/metabolismo
19.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922961

RESUMO

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.


Assuntos
Obesidade/terapia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Animais , Fármacos Antiobesidade/uso terapêutico , Cirurgia Bariátrica , Modelos Animais de Doenças , Heterozigoto , Humanos , Hiperfagia/genética , Camundongos , Mutação , Obesidade/genética , Receptores para Leptina/química , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
20.
Med Sci Monit ; 27: e928503, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33677465

RESUMO

BACKGROUND The association between leptin receptor (LEPR) polymorphisms and keloids is still unclear. Our study aimed to explore the association between LEPR gene polymorphisms and keloids in the Chinese Han population. MATERIAL AND METHODS We implemented a case-control study in a cohort of 352 keloid patients and 299 healthy controls to analyze the correlation between 4 SNPs (rs1137101, rs1938496, rs6588147, and rs7555955) and keloids. Genomic DNA was extracted from peripheral blood by using TGuide M16 (Tiangen). Genotyping of LEPR SNPs was performed using an improved multiple ligase detection reaction (iMLDR) by Shanghai Genesky Bio-Tech Co., Ltd. RESULTS We found that patients caring the AA genotype of rs1137101 and the CC genotype rs1938496 tend to have the increased risk of keloids (P=0.026, P=0.047). Carrying the GA, AA gene type, and G allele frequencies of rs7555955, patients were more likely to have to keloids (P=0.030, P=0.016, P=0.018, respectively). There were no significant differences in genotype distribution and allele frequencies of rs6588147 between cases and controls. The association of rs1137101 and rs7555955 under dominant, recessive, and allele models exhibited significant differences among family-history keloid patients, no-family-history keloid groups, and normal controls (χ²=6.471, P=0.039; χ²=6.477, P=0.039; χ²=6.197, P=0.045, respectively). Similarly, the OR of rs1137101 in the recessive model was significantly higher in patients with a family history of keloids than those in controls. Nonetheless, there are significant ORs of rs1938496 and rs6588147 among the mild-moderate keloid, severe keloid, and control groups. CONCLUSIONS The LEPR gene polymorphisms are associated with keloid formation and severity, especially in patients with a positive family history.


Assuntos
Queloide/genética , Receptores para Leptina/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Queloide/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores para Leptina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...