Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.674
Filtrar
1.
Arq Bras Cir Dig ; 33(1): e1497, 2020 Jul 08.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32667527

RESUMO

BACKGROUND: Effects of duodenal-jejunal bypass surgery (DJB) on the proliferation of nuclei and the area of adipocytes in the brown adipose tissue of obese rats. Thermogenic activity in the brown adipose tissue (BAT) of obese individuals is reduced, and this condition may be modified by bariatric surgery (BS). AIM: To characterize fat deposition in BAT from hypothalamic obese (HyO) rats submitted to duodenal-jejunal-bypass (DJB) surgery. METHODS: For induction of hypothalamic obesity, newborn male Wistar rats were treated with subcutaneous injections of monosodium glutamate (MSG). The control (CTL) group received saline solution. At 90 days, the HyO rats were submitted to DJB or sham operation, generating the HyO-DJB and HyO-SHAM groups. At 270 days, the rats were euthanized, and the BAT was weighed and submitted to histological analysis. RESULTS: Compared to BAT from CTL animals, the BAT from HyO-SHAM rats displayed increased weight, hypertrophy with greater lipid accumulation and a reduction in nucleus number. DJB effectively increased nucleus number and normalized lipid deposition in the BAT of HyO-SHAM rats, similar to that observed in CTL animals. CONCLUSION: DJB surgery avoided excessive lipid deposition in the BAT of hypothalamic obese rats, suggesting that this procedure could reactivate thermogenesis in BAT, and contribute to increase energy expenditure.


Assuntos
Tecido Adiposo Marrom , Derivação Gástrica , Tecido Adiposo , Animais , Glicemia , Duodeno , Lipídeos , Masculino , Obesidade , Ratos , Ratos Wistar
2.
Adv Exp Med Biol ; 1207: 445-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671767

RESUMO

The prevalence of obesity is increasing rapidly and is closely associated with a variety of metabolic diseases. Recent studies have suggested that autophagy is likely to play an important role in the development of obesity and may be related to insulin sensitivity. Autophagy may be involved in the browning of white adipose tissue and may also affect the metabolic balance of lipids. Autophagy can degrade cytoplasmic lipids by lipophagy in hepatocytes. Furthermore, Autophagy in hepatocytes helps prevent NAFLD. The study of autophagy in glucose metabolism is still in a very preliminary stage. Changes in autophagy activity play an important role in the development of insulin resistance in diabetes and many metabolic diseases. Therefore, it is still worth further exploration on the deeper mechanism of oxidative stress induction of insulin resistance to autophagy and whether there will be corresponding complications to the body.


Assuntos
Autofagia , Diabetes Mellitus , Obesidade , Tecido Adiposo Marrom , Tecido Adiposo Branco , Humanos , Resistência à Insulina
3.
Nat Commun ; 11(1): 3347, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620768

RESUMO

A sharp increase in mitochondrial Ca2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.


Assuntos
Adipócitos Marrons/patologia , Tecido Adiposo Marrom/metabolismo , Norepinefrina/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Termogênese/fisiologia , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/citologia , Adrenérgicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Temperatura Baixa/efeitos adversos , Ciclosporina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Microscopia Intravital , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Cultura Primária de Células , Transdução de Sinais , Trocador de Sódio e Cálcio/genética , Termogênese/efeitos dos fármacos
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 6-11, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476366

RESUMO

OBJECTIVE: To observe the effects of dihydromyricetin (DHM) on obesity induced by high-fat diet in mice, and to explore whether its mechanism of action is related to the promotion of WAT browning. METHODS: Sixty c57bl/6j mice were randomly divided into 6 groups (n=10): ①normal control group (ND group): normal feed feeding; ②Normal control + low dose DHM group (ND+L-DHM group): normal feed feeding was treated with low dose DHM (125 mg/(kg·d)); ③Normal control + high dose DHM group (ND+H-DHM group): normal feed feeding was treated with high dose DHM (250 mg/(kg·d)); ④High-fat diet group (HFD): high-fat diet; ⑤high-fat diet + low-dose DHM group (HFD+L-DHM group): high-fat diet feeding with low-dose DHM; ⑥High-fat diet + high-dose DHM group (HFD+H-DHM group): High-fat diet was treated with high-dose DHM. After 16 weeks, the mice were fasted overnight, blood samples were collected for fasting blood glucose and blood lipids, then the animals were sacrificed, body length was measured, and Lee's index was calculated. After weighing the adipose tissue in the scapula, groin and epididymis, formaldehyde fixation and HE staining were used to observe the fat cells size, immunohistochemistry was used to detect the expression of uncoupling protein 1 (UCP1). The body weight was measured every 4 weeks during the experiment. RESULTS: Compared with the ND group, the body weight of the mice in the HFD group was increased significantly, suggesting that the obese mouse model replicated successfully. In addition, the body fat weight, fat cell diameter, Lee's index and blood glucose of the HFD group were increased significantly, and the expression of UCP1 in the adipocytes was increased. Body weight, fat cell diameter, Lee's index and blood glucose of HFD mice treated with L-DHM and H-DHM were reversed significantly, while the expression of UCP1 in adipocytes was more significantly increased; however, L-DHM and H-DHM had no significant effects on the above indicators in normal mice. CONCLUSION: Dihydromyricetin inhibited high fat diet induced mouse obesity; the mechanism might be associated with promoting WAT browning.


Assuntos
Tecido Adiposo Marrom/fisiologia , Dieta Hiperlipídica , Flavonóis/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Peso Corporal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
5.
Eur J Endocrinol ; 183(3): 343-355, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32508310

RESUMO

Objective: Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women. Design: To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11). Methods: Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli. Results: Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17ß-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17ß-estradiol levels, but not with testosterone concentrations. Conclusions: Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17ß-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.


Assuntos
Tecido Adiposo Marrom/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Caracteres Sexuais , Termogênese/fisiologia , Adulto , Temperatura Corporal/fisiologia , Temperatura Baixa , Estradiol/sangue , Feminino , Fase Folicular/fisiologia , Humanos , Fase Luteal/fisiologia , Masculino , Refeições , Ciclo Menstrual/fisiologia , Estudos Retrospectivos , Testosterona/sangue , Adulto Jovem
6.
Nat Commun ; 11(1): 3097, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555194

RESUMO

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Medula Óssea/metabolismo , Glucose/metabolismo , Animais , Western Blotting , Feminino , Homeostase/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons , Ratos , Esqueleto/metabolismo
7.
Nat Commun ; 11(1): 2847, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504036

RESUMO

The browning of white adipose tissue (WAT) has got much attention for its potential beneficial effects on metabolic disorders, however, the nutritional factors and neuronal signals involved remain largely unknown. We sought to investigate whether WAT browning is stimulated by leucine deprivation, and whether the amino acid sensor, general control non-derepressible 2 (GCN2), in amygdalar protein kinase C-δ (PKC-δ) neurons contributes to this regulation. Our results show that leucine deficiency can induce WAT browning, which is unlikely to be caused by food intake, but is largely blocked by PKC-δ neuronal inhibition and amygdalar GCN2 deletion. Furthermore, GCN2 knockdown in amygdalar PKC-δ neurons blocks WAT browning, which is reversed by over-expression of amino acid responsive gene activating transcription factor 4 (ATF4), and is mediated by the activities of amygdalar PKC-δ neurons and the sympathetic nervous system. Our data demonstrate that GCN2/ATF4 can regulate WAT browning in amygdalar PKC-δ neurons under leucine deprivation.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Tecido Adiposo Branco/fisiologia , Tonsila do Cerebelo/fisiologia , Leucina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/inervação , Tonsila do Cerebelo/citologia , Animais , Técnicas de Silenciamento de Genes , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Proteína Quinase C-delta/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/fisiologia , Técnicas Estereotáxicas , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
8.
PLoS One ; 15(5): e0232084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374735

RESUMO

Knowledge about the mouse brown adipose tissue (BAT) proteome can provide a deeper understanding of the function of mammalian BAT. Herein, a comprehensive analysis of interscapular BAT from C57BL/6J female mice was conducted by 2DLC and high-resolution mass spectrometry to construct a comprehensive proteome dataset of mouse BAT proteins. A total of 4949 nonredundant proteins were identified, and 4495 were quantified using the iBAQ method. According to the iBAQ values, the BAT proteome was divided into high-, middle- and low-abundance proteins. The functions of the high-abundance proteins were mainly related to glucose and fatty acid oxidation to produce heat for thermoregulation, while the functions of the middle- and low-abundance proteins were mainly related to protein synthesis and apoptosis, respectively. Additionally, 497 proteins were predicted to have signal peptides using SignalP4 software, and 75 were confirmed in previous studies. This study, for the first time, comprehensively profiled and functionally annotated the BAT proteome. This study will be helpful for future studies focused on biomarker identification and BAT molecular mechanisms.


Assuntos
Tecido Adiposo Marrom/metabolismo , Anotação de Sequência Molecular , Proteoma/metabolismo , Proteômica , Tecido Adiposo Marrom/química , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Bases de Dados de Proteínas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Anotação de Sequência Molecular/métodos , Proteoma/análise , Proteômica/métodos , Espectrometria de Massas em Tandem
9.
PLoS One ; 15(5): e0232400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32384084

RESUMO

Metabolic parameters ranging from circulating nutrient levels and substrate utilization to energy expenditure and thermogenesis are temporally modulated by the circadian timing system. During critical embryonic developmental periods, maternal over-nutrition could alter key elements in different tissues associated with the generation of circadian rhythmicity, compromising normal rhythmicity development. To address this issue, we determine whether maternal over-nutrition leads to alterations in the development of circadian rhythmicity at physiological and behavioral levels in the offspring. For this, female rabbits were fed a standard diet (SD) or high-fat and carbohydrate diet (HFCD) before mating and during gestation. Core body temperature and gross locomotor activity were continuously recorded in newborn rabbits, daily measurements of body weight and the amount of milk ingested was carried out. At the end of lactation, tissue samples, including brown adipose tissue (BAT) and white adipose tissue (WAT), were obtained for determining the expression of uncoupling protein-1 (UCP1) and cell death-inducing DNA fragmentation factor-like effector A (CIDEA) genes. HFCD pups exhibited conspicuous differences in the development of the daily rhythm of temperature and locomotor activity compared to the SD pups, including a significant increase in the daily mean core temperature, changes in the time when temperature or activity remains above the average, shifts in the acrophase, decrease in the duration and intensity of the anticipatory rise previous to nursing, and changes in frequency of the rhythms. HFCD pups exhibited a significant increase in BAT thermogenesis markers, and a decrease of these markers in WAT, indicating more heat generation by brown adipocytes and alterations in the browning process. These results indicate that maternal over-nutrition alters offspring homeostatic and chronostatic regulation at the physiological and behavioral levels. Further studies are needed to determine whether these alterations are associated with the changes in the organization of the circadian system of the progeny.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Ritmo Circadiano/fisiologia , Lactação/fisiologia , Locomoção/fisiologia , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/fisiopatologia , Animais , Proteínas Reguladoras de Apoptose/genética , Regulação da Temperatura Corporal/genética , Ritmo Circadiano/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica , Lactação/genética , Locomoção/genética , Fenômenos Fisiológicos da Nutrição Materna , Hipernutrição/complicações , Hipernutrição/genética , Hipernutrição/fisiopatologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/fisiopatologia , Coelhos , Proteína Desacopladora 1/genética
10.
Metabolism ; 109: 154280, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473155

RESUMO

OBJECTIVE: Obesity is recognized as the cause of multiple metabolic diseases and is rapidly increasing worldwide. As obesity is due to an imbalance in energy homeostasis, the promotion of energy consumption through browning of white adipose tissue (WAT) has emerged as a promising therapeutic strategy to counter the obesity epidemic. However, the molecular mechanisms of the browning process are not well understood. In this study, we investigated the effects of the GATA family of transcription factors on the browning process. METHODS: We used qPCR to analyze the expression of GATA family members during WAT browning. In order to investigate the function of GATA3 in the browning process, we used the lentivirus system for the ectopic expression and knockdown of GATA3. Western blot and real-time qPCR analyses revealed the regulation of thermogenic genes upon ectopic expression and knockdown of GATA3. Luciferase reporter assays, co-immunoprecipitation, and chromatin immunoprecipitation were performed to demonstrate that GATA3 interacts with proliferator-activated receptor-γ co-activator-1α (PGC-1α) to regulate the promoter activity of uncoupling protein-1 (UCP-1). Enhanced energy expenditure by GATA3 was confirmed using oxygen consumption assays, and the mitochondrial content was assessed using MitoTracker. Furthermore, we examined the in vivo effects of lentiviral GATA3 overexpression and knockdown in inguinal adipose tissue of mice. RESULTS: Gata3 expression levels were significantly elevated in the inguinal adipose tissue of mice exposed to cold conditions. Ectopic expression of GATA3 enhanced the expression of UCP-1 and thermogenic genes upon treatment with norepinephrine whereas GATA3 knockdown had the opposite effect. Luciferase reporter assays using the UCP-1 promoter region showed that UCP-1 expression was increased in a dose-dependent manner by GATA3 regardless of norepinephrine treatment. GATA3 was found to directly bind to the promoter region of UCP-1. Furthermore, our results indicated that GATA3 interacts with the transcriptional coactivator PGC-1α to increase the expression of UCP-1. Taken together, we demonstrate that GATA3 has an important role in enhancing energy expenditure by increasing the expression of thermogenic genes both in vitro and in vivo. CONCLUSION: GATA3 may represent a promising target for the prevention and treatment of obesity by regulating thermogenic capacity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Fator de Transcrição GATA3/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína Desacopladora 1/metabolismo , Animais , Temperatura Baixa , Metabolismo Energético , Fator de Transcrição GATA3/genética , Humanos , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Regiões Promotoras Genéticas , Termogênese/genética , Proteína Desacopladora 1/genética , Regulação para Cima
11.
PLoS One ; 15(5): e0225488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453751

RESUMO

For (metabolic) research models using mice, singly housing is widely used for practical purposes to study e.g. energy balance regulation and derangements herein. Mouse (social) housing practices could however influence study results by modulating (metabolic) health outcomes. To study the effects of the social housing condition, we assessed parameters for energy balance regulation and proneness to (diet induced) obesity in male C57Bl/6J mice that were housed individually or socially (in pairs) directly after weaning, both at standard ambient temperature of 21°C. During adolescence, individually housed mice had reduced growth rate, while energy intake and energy expenditure were increased compared to socially housed counterparts. At 6 weeks of age, these mice had reduced lean body mass, but significantly higher white adipose tissue mass compared to socially housed mice, and higher UCP-1 mRNA expression in brown adipose tissue. During adulthood, body weight gain of individually housed animals exceeded that of socially housed mice, with elevations in both energy intake and expenditure. At 18 weeks of age, individually housed mice showed higher adiposity and higher mRNA expression of UCP-1 in inguinal white but not in brown adipose tissue. Exposure to an obesogenic diet starting at 6 weeks of age further amplified body weight gain and adipose tissue deposition and caused strong suppression of inguinal white adipose tissue mRNA UCP-1 expression. This study shows that post-weaning individual housing of male mice impairs adolescent growth and results in higher susceptibility to obesity in adulthood with putative roles for thermoregulation and/or affectiveness.


Assuntos
Metabolismo Energético , Abrigo para Animais , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal , Regulação da Temperatura Corporal , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Energia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desmame
12.
Nat Commun ; 11(1): 2379, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404872

RESUMO

Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/deficiência , Temperatura Baixa , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Marrons/ultraestrutura , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação/genética , Células Cultivadas , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética
13.
Metabolism ; 108: 154261, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32407726

RESUMO

BACKGROUND: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. METHODS: Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. RESULTS: Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. CONCLUSIONS: Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.


Assuntos
Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo Marrom/metabolismo , Lipogênese/fisiologia , Proteínas/metabolismo , Adipócitos Bege/metabolismo , Células Cultivadas , Estudos Transversais , Feminino , Humanos , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Proteína Desacopladora 1/metabolismo , Regulação para Cima/fisiologia
14.
Nat Commun ; 11(1): 2132, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358539

RESUMO

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein-kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Calicreínas/metabolismo , Cininas/metabolismo , Animais , Bradicinina/genética , Bradicinina/metabolismo , Sistema Endócrino/metabolismo , Imunofluorescência , Calicreínas/genética , Cininogênios/genética , Cininogênios/metabolismo , Cininas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
15.
Nat Commun ; 11(1): 2306, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385399

RESUMO

During ß-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62-/- and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Proteína Sequestossoma-1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adipogenia/fisiologia , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/diagnóstico por imagem , Tecido Adiposo Branco/metabolismo , Animais , Núcleo Celular/metabolismo , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ligação Proteica , Proteína Sequestossoma-1/genética , Proteína Desacopladora 1/metabolismo
16.
Gac Med Mex ; 156(2): 142-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32285854

RESUMO

Adipose tissue is an endocrine organ with high metabolic activity. Countless adipose tissue-secreted adipokines and lipokines, as well as peptides and lipids with biological activity have thus far been discovered. Both white and brown and beige adipose tissue are known to contribute to energy homeostasis and metabolic regulation. The purpose of this review is to report on the most recent findings related to adipose tissue according to its color and its relationship with metabolic alterations associated with obesity. After a review of the specialized literature, white, brown and beige adipocyte populations were identified to be able to coexist within the same structure, and to modify global metabolic state in physiological or pathological situations.


Assuntos
Tecido Adiposo Bege , Tecido Adiposo Marrom , Tecido Adiposo Branco , Cor
17.
Nat Commun ; 11(1): 1517, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251290

RESUMO

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fígado Gorduroso/patologia , Resistência à Insulina , Neurônios/metabolismo , Obesidade/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Feminino , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Humanos , Hipotálamo/patologia , Leptina/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Receptores para Leptina/metabolismo , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
18.
PLoS One ; 15(4): e0231650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315370

RESUMO

Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.


Assuntos
Tecido Adiposo Marrom/crescimento & desenvolvimento , Desenvolvimento Fetal/genética , Resistência à Insulina/genética , Fígado/metabolismo , Tecido Adiposo Marrom/efeitos da radiação , Animais , Glicemia/metabolismo , Metabolismo dos Carboidratos/genética , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Desenvolvimento Fetal/efeitos da radiação , Feto , Glucose/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/efeitos da radiação , Fígado/patologia , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Radiação
20.
Nat Commun ; 11(1): 1642, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242025

RESUMO

Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Herein, we identify adipocyte-expressed apoptosis signal-regulating kinase 1 (ASK1) as regulator of adipose tissue browning. High fat diet-fed adipocyte-specific ASK1 knockout mice reveal increased UCP1 protein levels in inguinal adipose tissue concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. In addition, ASK1-depletion blunts LPS-mediated downregulation of isoproterenol-induced UCP1 in subcutaneous fat both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression in chow-fed mice attenuates cold-induced UCP1 protein levels in inguinal fat. Mechanistically, ASK1 phosphorylates interferon regulatory factor 3 (IRF3) resulting in reduced Ucp1 expression. Taken together, our studies unravel a role of ASK1 in mediating the inhibitory effect of caloric surplus or LPS-treatment on adipose tissue browning. Adipocyte ASK1 might be a pharmacological target to combat obesity and associated morbidities.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Obesidade/metabolismo , Animais , Metabolismo Energético , Feminino , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , MAP Quinase Quinase Quinase 5/genética , Masculino , Camundongos , Camundongos Knockout , Obesidade/genética , Fosforilação , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA