Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417460

RESUMO

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Restrição Calórica , Linhagem Celular , Colforsina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagon/metabolismo , Glucocorticoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicosilação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Ácido Pirúvico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
2.
Nutr Diabetes ; 11(1): 4, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414371

RESUMO

BACKGROUND/OBJECTIVES: Catch-up growth, an important risk factor for later obesity and type 2 diabetes, is often characterized by a high rate of fat deposition associated with hyperinsulinemia and glucose intolerance. We tested here the hypothesis that refeeding on a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) improves glucose homeostasis primarily by enhancing insulin sensitivity in skeletal muscles and adipose tissues. METHODS: Rats were caloric restricted for 2 weeks followed by 1-2 weeks of isocaloric refeeding on either a low-fat (LF) diet, a high-fat (HF) diet based on animal fat and high in saturated and monounsaturated fatty acids (HF SMFA diet), or a HF diet based on vegetable oils (1:1 mixture of safflower and linseed oils) and rich in the essential fatty acids linoleic and α-linolenic acids (HF ePUFA diet). In addition to measuring body composition and a test of glucose tolerance, insulin sensitivity was assessed during hyperinsulinemic-euglycemic clamps at the whole-body level and in individual skeletal muscles and adipose tissue depots. RESULTS: Compared to animals refed the LF diet, those refed the HF-SMFA diet showed a higher rate of fat deposition, higher plasma insulin and glucose responses during the test of glucose tolerance, and markedly lower insulin-stimulated glucose utilization at the whole body level (by a-third to a-half) and in adipose tissue depots (by 2-5 folds) during insulin clamps. While refeeding on the ePUFA diet prevented the increases in fat mass and in plasma insulin and glucose, the results of insulin clamps revealed that insulin-stimulated glucose utilization was not increased in skeletal muscles and only marginally higher in adipose tissues and at the whole-body level. CONCLUSIONS: These results suggest only a minor role for enhanced insulin sensitivity in the mechanisms by which diets high in ePUFA improves glucose homeostasis during catch-up growth.


Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Dieta Hiperlipídica/métodos , Ácidos Graxos Insaturados/administração & dosagem , Resistência à Insulina , Músculo Esquelético/metabolismo , Animais , Peso Corporal , Dieta com Restrição de Gorduras , Gorduras na Dieta/administração & dosagem , Glucose/metabolismo , Técnica Clamp de Glucose , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase , Hiperinsulinismo/metabolismo , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley
3.
Nat Commun ; 11(1): 5808, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199701

RESUMO

Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.


Assuntos
Biocatálise , Homeostase , Metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-vav/metabolismo , Transdução de Sinais , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Biocatálise/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Genótipo , Glucose/farmacologia , Homeostase/efeitos dos fármacos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo
4.
Antioxid Redox Signal ; 32(9): 618-635, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-31931619

RESUMO

Aims: Nicotinamide adenine dinucleotide phosphate oxidases (NOX-es) produce reactive oxygen species and modulate ß-cell insulin secretion. Islets of type 2 diabetic subjects present elevated expression of NOX5. Here, we sought to characterize regulation of NOX5 expression in human islets in vitro and to uncover the relevance of NOX5 in islet function in vivo using a novel mouse model expressing NOX5 in doxycycline-inducible, ß-cell-specific manner (RIP/rtTA/NOX5 mice). Results: In situ hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 messenger ribonucleic acid (mRNA) and protein expressions in human islets. In cultures of dispersed islets, NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8 mM glucose) conditions. Small interfering ribonucleic acid (siRNA)-mediated knockdown of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion (GIIS) in vitro. However, when islets were preincubated in high (16.7 mM) glucose media for 12 h, NOX5 appeared also in insulin-positive (ß) cells. In vivo, mice with ß-cell NOX5 expression developed aggravated impairment of GIIS compared with control mice when challenged with 14 weeks of high-fat diet. Similarly, in vitro palmitate preincubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared with their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation, suggesting impaired cyclic adenosine monophosphate (cAMP)-mediated signaling due to increased phosphodiesterase activation. Innovation and Conclusions: Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell-mediated intraislet crosstalk in physiological circumstances but also identifying it as an aggravating factor in ß-cell failure in diabetic conditions.

5.
Nat Commun ; 10(1): 3545, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391467

RESUMO

Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that S100A9, also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of S100A9 alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of S100A9. Thus, our data identify the S100A9/TLR4 axis as a putative target for ID care.


Assuntos
Calgranulina B/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo , Longevidade/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Toxina Diftérica/toxicidade , Ácidos Graxos/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Insulina/deficiência , Leptina/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Oxirredução , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estreptozocina/toxicidade , Receptor 4 Toll-Like/genética
6.
Cell Rep ; 27(8): 2385-2398.e3, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31116983

RESUMO

Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet the brain and peripheral pathways linking proper insulin effect to diurnal changes in light-dark and feeding-fasting inputs are poorly understood. Here, we show that the insulin sensitivity of several metabolically relevant tissues fluctuates during the 24 h period. For example, in mice, the insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function.


Assuntos
Insulina/metabolismo , Músculo Esquelético/metabolismo , Fototerapia/métodos , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Animais , Ritmo Circadiano , Humanos , Camundongos
7.
Cell Metab ; 28(6): 907-921.e7, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30174308

RESUMO

Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4-/- bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4-/- or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.


Assuntos
Tecido Adiposo Bege/metabolismo , Proteínas de Bactérias/metabolismo , Restrição Calórica , Fígado Gorduroso/metabolismo , Microbioma Gastrointestinal , Trato Gastrointestinal , Lipídeo A/metabolismo , Tecido Adiposo Bege/citologia , Animais , Eosinófilos/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/metabolismo
8.
Nat Commun ; 8(1): 1820, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29180649

RESUMO

Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Obesidade/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Adulto , Idoso , Animais , Glicemia , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Células Hep G2 , Humanos , Inflamação/metabolismo , Insulina/sangue , Interleucina-6/metabolismo , Metabolismo dos Lipídeos , Lipopolissacarídeos/efeitos adversos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Modelos Animais , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/complicações , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/biossíntese , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Sirtuína 1/metabolismo
9.
PLoS One ; 11(9): e0162517, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27618559

RESUMO

Physiological processes at adulthood, such as energy metabolism and insulin sensitivity may originate before or weeks after birth. These underlie the concept of fetal and/or neonatal programming of adult diseases, which is particularly relevant in the case of obesity and type 2 diabetes. The aim of this study was to determine the impact of a perinatal high fat diet on energy metabolism and on leptin as well as insulin sensitivity, early in life and at adulthood in two strains of rats presenting different susceptibilities to diet-induced obesity. The impact of a perinatal high fat diet on glucose tolerance and diet-induced obesity was also assessed. The development of glucose intolerance and of increased fat mass was confirmed in the obesity-prone Wistar rat, even after 28 days of age. By contrast, in obesity-resistant Lou/C rats, an improved early leptin signaling may be responsible for the lack of deleterious effect of the perinatal high fat diet on glucose tolerance and increased adiposity in response to high fat diet at adulthood. Altogether, this study shows that, even if during the perinatal period adaptation to the environment appears to be genetically determined, adaptive mechanisms to nutritional challenges occurring at adulthood can still be observed in rodents.


Assuntos
Dieta Hiperlipídica , Leptina/metabolismo , Obesidade/genética , Período Pós-Parto , Transdução de Sinais , Animais , Glicemia/metabolismo , Feminino , Teste de Tolerância a Glucose , Masculino , Gravidez , Ratos , Ratos Wistar
10.
Cell Metab ; 24(3): 434-446, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27568549

RESUMO

Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra(-/-), Stat6(-/-), or mice transplanted with Stat6(-/-) bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Restrição Calórica , Imunidade , Transdução de Sinais/imunologia , Tecido Adiposo Bege/metabolismo , Animais , Dieta , Comportamento Alimentar , Glucose/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Obesos , Gordura Subcutânea/metabolismo , Termogênese
11.
Cell Physiol Biochem ; 38(3): 1218-25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26982498

RESUMO

BACKGROUND/AIMS: Fibroblast growth factor 21 (FGF21), a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. METHODS: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. RESULTS: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. CONCLUSION: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Masculino , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo
12.
Cell ; 163(6): 1360-74, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26638070

RESUMO

Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.


Assuntos
Metabolismo Energético , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/fisiologia , Homeostase , Tecido Adiposo Branco/metabolismo , Animais , Apoptose , Temperatura Baixa , Enterócitos/citologia , Enterócitos/metabolismo , Vida Livre de Germes , Resistência à Insulina , Absorção Intestinal , Camundongos , Verrucomicrobia/metabolismo
13.
Nat Med ; 21(12): 1497-1501, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26569380

RESUMO

Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient (ob/ob) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic-treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Microbiota , Obesidade/microbiologia , Obesidade/patologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Tamanho Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Vida Livre de Germes , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/farmacologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
14.
Diabetes ; 64(11): 3700-12, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26224884

RESUMO

Brown adipose tissue (BAT), characterized by the presence of uncoupling protein 1 (UCP1), has been described as metabolically active in humans. Lou/C rats, originating from the Wistar strain, are resistant to obesity. We previously demonstrated that Lou/C animals express UCP1 in beige adipocytes in inguinal white adipose tissue (iWAT), suggesting a role of this protein in processes such as the control of body weight and the observed improved insulin sensitivity. A ß3 adrenergic agonist was administered for 2 weeks in Wistar and Lou/C rats to activate UCP1 and delineate its metabolic impact. The treatment brought about decreases in fat mass and improvements in insulin sensitivity in both groups. In BAT, UCP1 expression increased similarly in response to the treatment in the two groups. However, the intervention induced the appearance of beige cells in iWAT, associated with a marked increase in UCP1 expression, in Lou/C rats only. This increase was correlated with a markedly enhanced glucose uptake measured during euglycemic-hyperinsulinemic clamps, suggesting a role of beige cells in this process. Activation of UCP1 in ectopic tissues, such as beige cells in iWAT, may be an interesting therapeutic approach to prevent body weight gain, decrease fat mass, and improve insulin sensitivity.


Assuntos
Tecido Adiposo Branco/metabolismo , Resistência à Insulina/fisiologia , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Dioxóis/farmacologia , Canais Iônicos/genética , Masculino , Proteínas Mitocondriais/genética , Obesidade/genética , Ratos , Ratos Wistar , Termogênese/efeitos dos fármacos , Termogênese/fisiologia , Proteína Desacopladora 1
15.
Front Physiol ; 6: 4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25688211

RESUMO

Presence of brown adipose tissue (BAT), characterized by the expression of the thermogenic uncoupling protein 1 (UCP1), has recently been described in adult humans. UCP1 is expressed in classical brown adipocytes, as well as in "beige cells" in white adipose tissue (WAT). The thermogenic activity of BAT is mainly controlled by the sympathetic nervous system. Endocrine factors, such as fibroblast growth factor 21 (FGF21) and bone morphogenic protein factor-9 (BMP-9), predominantly produced in the liver, were shown to lead to activation of BAT thermogenesis, as well as to "browning" of WAT. This was also observed in response to irisin, a hormone secreted by skeletal muscles. Different approaches were used to delineate the impact of UCP1 on insulin sensitivity. When studied under thermoneutral conditions, UCP1 knockout mice exhibited markedly increased metabolic efficiency due to impaired thermogenesis. The impact of UCP1 deletion on insulin sensitivity in these mice was not reported. Conversely, several studies in both rodents and humans have shown that BAT activation (by cold exposure, ß3-agonist treatment, transplantation and others) improves glucose tolerance and insulin sensitivity. Interestingly, similar results were obtained by adipose tissue-specific overexpression of PR-domain-containing 16 (PRDM16) or BMP4 in mice. The mediators of such beneficial effects seem to include FGF21, interleukin-6, BMP8B and prostaglandin D2 synthase. Interestingly, some of these molecules can be secreted by BAT itself, indicating the occurrence of autocrine effects. Stimulation of BAT activity and/or recruitment of UCP1-positive cells are therefore relevant targets for the treatment of obesity/type 2 diabetes in humans.

16.
Endocrinology ; 155(11): 4189-201, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25157455

RESUMO

Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin (TGOT) and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined.


Assuntos
Adiposidade/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/tratamento farmacológico , Ocitocina/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Glucose/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/metabolismo , Ocitocina/administração & dosagem , Magreza/metabolismo , Magreza/patologia
17.
Mol Genet Metab ; 112(1): 64-72, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24685552

RESUMO

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and ß2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7ß2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7ß2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7ß2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7ß2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central ß2nAChR deficiency.


Assuntos
Tecido Adiposo/metabolismo , Glucose/metabolismo , Ilhotas Pancreáticas/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Índice Glicêmico , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Receptores Nicotínicos/genética
18.
PLoS One ; 8(9): e73452, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24039946

RESUMO

The Lou/C rat, an inbred strain of Wistar origin, was described as a model of resistance to age- and diet-induced obesity. Although such a resistance involves many metabolic parameters described in our previous studies, Lou/C rats also exhibit a spontaneous food restriction due to decreased food consumption during the nocturnal period. We then attempted to delineate the leptin sensitivity and mechanisms implicated in this strain, using different protocols of acute central and peripheral leptin administration. A first analysis of the meal patterns revealed that Lou/C rats eat smaller meals, without any change in meal number compared to age-matched Wistar animals. Although the expression of the recognized leptin transporters (leptin receptors and megalin) measured in the choroid plexus was normal in Lou/C rats, the decreased triglyceridemia observed in these animals is compatible with an increased leptin transport across the blood brain barrier. Improved hypothalamic leptin signaling in Lou/C rats was also suggested by the higher pSTAT3/STAT3 (signal transducer and activator of transcription 3) ratio observed following acute peripheral leptin administration, as well as by the lower hypothalamic mRNA expression of the suppressor of cytokine signaling 3 (SOCS3), known to downregulate leptin signaling. To conclude, spontaneous hypophagia of Lou/C rats appears to be related to improved leptin sensitivity. The main mechanism underlying such a phenomenon consists in improved leptin signaling through the Ob-Rb leptin receptor isoform, which seems to consequently lead to overexpression of brain-derived neurotrophic factor (BDNF) and thyrotropin-releasing hormone (TRH).


Assuntos
Ingestão de Alimentos , Leptina/metabolismo , Obesidade/metabolismo , Animais , Hipotálamo/metabolismo , Masculino , Obesidade/genética , Obesidade/fisiopatologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores para Leptina/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/genética
19.
Neuropeptides ; 47(3): 163-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23410741

RESUMO

The effects of aging and long-term caloric restriction (LTCR), on the regulation of neuropeptide Y (NPY) Y1, Y2 and Y5 receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12 months. [(125)I]GR231118, a Y1 antagonist was used as Y1 receptor radioligand. [(125)I][Leu(31), Pro(34)]PYY, a high affinity agonist of Y1 and Y5 subtypes was used in the absence or presence of 100 nM BIBO3304 (a highly selective Y1 receptor antagonist) to assess the apparent levels of [(125)I][Leu(31), Pro(34)]PYY/BIBO3304 insensitive sites (Y5-like) from [(125)I][Leu(31), Pro(34)]PYY/BIBO3304 sensitive sites (Y1). [(125)I]PYY(3-36) was used to label the Y2 receptor. In the brain of 3-month-old AL rats, the distribution and densities of Y1, Y2 and Y5 receptors were in agreement with previous reports. In the brain of 20AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed. In contrast, LTCR had multiple effects. It induced specific decreases of Y1-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y2-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y1-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y2-receptor densities in the CA2 subfield of the hippocampus. These results indicate that LTCR not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions.


Assuntos
Envelhecimento/fisiologia , Química Encefálica/fisiologia , Encéfalo/crescimento & desenvolvimento , Restrição Calórica , Receptores de Neuropeptídeo Y/metabolismo , Animais , Autorradiografia , Sítios de Ligação/efeitos dos fármacos , Dieta , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiologia , Peptídeo YY/metabolismo , Peptídeos Cíclicos/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Diabetes ; 62(2): 362-72, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22961086

RESUMO

Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Glucose/metabolismo , Homeostase/fisiologia , Lipogênese/fisiologia , Síndrome da Realimentação/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Hiperinsulinismo/metabolismo , Hiperfagia/metabolismo , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...