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1.
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
2.
Plast Reconstr Surg ; 145(5): 1183-1195, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32332538

RESUMO

BACKGROUND: Growing evidence has demonstrated that adipose-derived stem cell-derived extracellular vesicles enhance the survival of fat grafts and the browning of white adipose tissue. We evaluated whether supplementation with adipose-derived stem cell-derived extracellular vesicles promotes the survival and browning of fat grafts. METHODS: Extracellular vesicles derived from adipose-derived stem cells were injected into fat grafts of C57BL/6 mice once per week until postgraft week 12. The grafts were collected and weighed after postgraft weeks 2, 4, and 12. The histological morphology, neovascularization, and the proportion of M2 macrophages of grafts were evaluated. The ability of extracellular vesicles to promote macrophage polarization and catecholamine secretion was detected. Whether the inducement of browning adipose differentiation is extracellular vesicles or the paracrine effect of M2 macrophages polarized by extracellular vesicles was also verified. RESULTS: Grafts treated by extracellular vesicles derived from adipose-derived stem cells showed enhanced beige adipose regeneration with increased neovascularization, M2 macrophage proportion, and norepinephrine secretion at postgraft week 4. Increased retention and decreased fibrosis and necrosis were noted at postgraft week 12. The extracellular vesicles uptake by macrophages promoted M2 type polarization and catecholamine secretion while suppressing M1 type polarization. Of note, browning adipose differentiation with enhanced energy expenditure could be promoted only by the conditioned medium from extracellular vesicle-polarized M2 macrophages but not by extracellular vesicles themselves. CONCLUSIONS: Supplementation with extracellular vesicles derived from adipose-derived stem cells increases fat graft survival and browning by which extracellular vesicles-polarized M2 macrophages secrete catecholamines to promote beige adipose regeneration.


Assuntos
Tecido Adiposo Bege/fisiologia , Tecido Adiposo Branco/transplante , Vesículas Extracelulares/transplante , Sobrevivência de Enxerto/fisiologia , Células-Tronco/citologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/fisiologia , Adulto , Animais , Catecolaminas/metabolismo , Diferenciação Celular , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Regeneração , Adulto Jovem
3.
FASEB J ; 34(1): 474-493, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914704

RESUMO

The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological, and metabolic analyses in ROCK2+/- and ROCK2+/KD mouse models, the latter harboring an allele with a kinase-dead (KD) mutation. Both ROCK2+/- and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/- mice on a high-fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/- stromal-vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro-beige phenotype of ROCK2+/- SV cells. In conclusion, ROCK2 activity-mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age-related and diet-induced fat mass gain and insulin resistance.


Assuntos
Adipogenia/fisiologia , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Resistência à Insulina , Obesidade/fisiopatologia , Termogênese/fisiologia , Quinases Associadas a rho/fisiologia , Animais , Diferenciação Celular , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Camundongos , Camundongos Knockout , Obesidade/etiologia , Transdução de Sinais
4.
DNA Cell Biol ; 38(11): 1303-1312, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553232

RESUMO

Growth differentiation factor 5 (GDF5) was reported to regulate brown adipogenesis; however, its effects on insulin sensitivity, full metabolic syndrome spectrum, and the thermogenesis in subcutaneous white adipose tissue (sWAT) have not been elucidated yet. We thus generated fatty acid-binding protein 4 (Fabp4)-GDF5 transgenic (TG) mice and showed that GDF5 TG mice developed a relative lean phenotype on a high-fat diet (HFD) and showed increased insulin sensitivity. Over expression of GDF5 in adipose tissues greatly promoted the thermogenic process in sWAT after cold or ß3-agonist treatment. In TG mice, sWAT showed an important thermogenic effect as the thermogenic gene expression was markedly increased, which was consistent with the typical features of beige adipocytes. Moreover, knockdown of the protein GDF5 impaired browning program in sWAT after thermogenic stimuli. Enhanced mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling was also identified in sWAT of HFD-fed GDF5 mice, and thermogenesis in mature adipocytes induced by GDF5 protein could be partly blocked by a p38 MAPK inhibitor. Taken together, our data suggest that GDF5 could improve insulin sensitivity and prevent metabolic syndrome, the adaptive thermogenesis in sWAT could mediate the obesity resistance effects of GDF5 in mice and partially resulted in the activation of the p38 MAPK signaling pathway.


Assuntos
Tecido Adiposo Branco/fisiologia , Fator 5 de Diferenciação de Crescimento/fisiologia , Termogênese/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Células Cultivadas , Fator 5 de Diferenciação de Crescimento/genética , Resistência à Insulina/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais/genética
5.
Adv Exp Med Biol ; 1178: 207-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493229

RESUMO

Growth hormone (GH) is a metabolic hormone that has major functions in the liver, muscle, and adipose tissue (AT). In the past 20 years, numerous studies have demonstrated that decreased growth hormone (GH) action is clearly linked to alterations in longevity. Therefore, it is not surprising that mechanisms underlying the extended longevity of GH-mutant animals include alterations in AT function. This Review aims to describe the basics of AT biology, GH secretion and action, and the effects of altered GH signaling in mice and humans. Lastly, this Review discusses the intersection of GH and AT, and how the influence of GH on AT may play a critical role in determining lifespan and healthspan.


Assuntos
Tecido Adiposo Marrom , Hormônio do Crescimento , Longevidade , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Hormônio do Crescimento/genética , Humanos , Longevidade/fisiologia , Camundongos , Transdução de Sinais
6.
Biomed Environ Sci ; 32(8): 578-591, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31488234

RESUMO

OBJECTIVE: We aimed to explore how fermented barley extracts with Lactobacillus plantarum dy-1 (LFBE) affected the browning in adipocytes and obese rats. METHODS: In vitro, 3T3-L1 cells were induced by LFBE, raw barley extraction (RBE) and polyphenol compounds (PC) from LFBE to evaluate the adipocyte differentiation. In vivo, obese SD rats induced by high fat diet (HFD) were randomly divided into three groups treated with oral gavage: (a) normal control diet with distilled water, (b) HFD with distilled water, (c) HFD with 800 mg LFBE/kg body weight (bw). RESULTS: In vitro, LFBE and the PC in the extraction significantly inhibited adipogenesis and potentiated browning of 3T3-L1 preadipocytes, rather than RBE. In vivo, we observed remarkable decreases in the body weight, serum lipid levels, white adipose tissue (WAT) weights and cell sizes of brown adipose tissues (BAT) in the LFBE group after 10 weeks. LFBE group could gain more mass of interscapular BAT (IBAT) and promote the dehydrogenase activity in the mitochondria. And LFBE may potentiate process of the IBAT thermogenesis and epididymis adipose tissue (EAT) browning via activating the uncoupling protein 1 (UCP1)-dependent mechanism to suppress the obesity. CONCLUSION: These results demonstrated that LFBE decreased obesity partly by increasing the BAT mass and the energy expenditure by activating BAT thermogenesis and WAT browning in a UCP1-dependent mechanism.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/metabolismo , Lactobacillus plantarum/química , Obesidade/tratamento farmacológico , Probióticos/metabolismo , Proteína Desacopladora 1/metabolismo , Células 3T3 , Adipócitos/fisiologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/fisiologia , Ração Animal/análise , Animais , Fármacos Antiobesidade/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Dieta , Fermentação , Hordeum/química , Masculino , Camundongos , Obesidade/genética , Extratos Vegetais/química , Probióticos/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteína Desacopladora 1/genética
7.
Scand J Med Sci Sports ; 29(11): 1699-1706, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31282585

RESUMO

BACKGROUND: Exercise training may improve energy expenditure, thermogenesis, and oxidative capacities. Therefore, we hypothesized that physical training enhances white adipose tissue mitochondrial oxidative capacity from obese women. OBJECTIVE: To evaluate mitochondrial respiratory capacity, mitochondrial content, and UCP1 gene expression in white adipose tissue from women with obesity before and after the physical training program. METHODS: Women (n = 14, BMI 33 ± 3 kg/m2 , 35 ± 6 years, mean ± SD) were submitted to strength and aerobic exercises (75%-90% maximum heart rate and multiple repetitions), 3 times/week during 8 weeks. All evaluated subjects were paired, before and after training for resting metabolic rate (RMR), substrate oxidation (lipid and carbohydrate) by indirect calorimeter, deuterium oxide body composition, and aerobic maximum velocity (Vmax ) test. At the beginning and at the ending of the protocol, abdominal subcutaneous adipose tissue was collected to measure the mitochondrial respiration by high-resolution respirometry, mitochondrial content by citrate synthase (CS) activity, and UCP1 gene expression by RT-qPCR. RESULTS: Combined physical training increased RMR, lipid oxidation, and Vmax but did not change body weight/composition. In WAT, exercise increased CS activity, decreased mitochondrial uncoupled respiration and mRNA of UCP1. RMR was positively correlated with fat-free mass. CONCLUSION: Physical training promotes an increase in mitochondrial content without changing tissue respiratory capacity, a reduction in mitochondrial uncoupling degree and UCP1 mRNA expression in WAT. Finally, it improved the resting metabolic rate, lipid oxidation and physical performance, independent of the body changing free, or fat mass in obese women.


Assuntos
Tecido Adiposo Branco/fisiologia , Exercício Físico , Mitocôndrias/fisiologia , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo , Adulto , Metabolismo Basal , Composição Corporal , Feminino , Humanos , Metabolismo dos Lipídeos , Oxirredução , Consumo de Oxigênio
8.
Mol Nutr Food Res ; 63(17): e1900403, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31206248

RESUMO

SCOPE: Targeting gut microbiota dysbiosis by prebiotics is effective, though side effects such as abdominal bloating and flatulence may arise following high prebiotic consumption over weeks. The aim is therefore to optimize the current protocol for prebiotic use. METHODS AND RESULTS: To examine the prebiotic properties of plant extracts, two independent studies are conducted in ob/ob mice, over two weeks. In the first study, Porphyra umbilicalis and Melissa officinalis L. extracts are evaluated; in the second study, a high vs low dose of an Emblica officinalis Gaertn extract is assessed. These plant extracts affect gut microbiota, caecum metabolome, and induce a significant lower plasma triacylglycerols (TG) following treatment with P. umbilicalis and significantly higher plasma free fatty acids (FFA) following treatment with the low-dose of E. officinalis Gaertn. Glucose- and insulin-tolerance are not affected but white adipose tissue and liver gene expression are modified. In the first study, IL-6 hepatic gene expression is significantly (adjusted p = 0.0015) and positively (r = 0.80) correlated with the bacterial order Clostridiales in all mice. CONCLUSION: The data show that a two-week treatment with plant extracts affects the dysbiotic gut microbiota and changes both caecum metabolome and markers of lipid metabolism in ob/ob mice.


Assuntos
Ceco/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/fisiologia , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Ceco/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Fígado/efeitos dos fármacos , Fígado/fisiologia , Masculino , Melissa/química , Camundongos Endogâmicos C57BL , Camundongos Obesos , Phyllanthus emblica/química , Porphyra/química , Prebióticos , Fatores de Tempo
9.
Am J Physiol Regul Integr Comp Physiol ; 317(1): R49-R58, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995083

RESUMO

The hypertensive pregnancy disorder preeclampsia (PE) is a leading cause of fetal and maternal morbidity/mortality. Obesity increases the risk to develop PE, presumably via the release of inflammatory mediators from the adipose tissue, but the exact etiology remains largely unknown. Using obese PE-like blood pressure high subline 5 (BPH/5) and lean gestational age-matched C57Bl6 mice, we aimed to obtain insight into differential reproductive white adipose tissue (rWAT) gene expression, circulating lipids and inflammation at the maternal-fetal interface during early pregnancy. In addition, we investigated the effect of 7 days 25% calorie restriction (CR) in early pregnancy on gene expression in rWAT and implantation sites. Compared with C57Bl6, female BPH/5 are dyslipidemic before pregnancy and show an amplification of rWAT mass, circulating cholesterol, free fatty acids, and triacylglycerol levels throughout pregnancy. RNA sequencing showed that pregnant BPH/5 mice have elevated gene enrichment in pathways related to inflammation and cholesterol biosynthesis at embryonic day (e) 7.5. Expression of cholesterol-related HMGCS1, MVD, Cyp51a1, and DHCR was validated by quantitative reverse-transcription-polymerase chain reaction. CR during the first 7 days of pregnancy restored the relative mRNA expression of these genes to a level comparable to C57Bl6 pregnant females and reduced the expression of circulating leptin and proinflammatory prostaglandin synthase 2 in both rWAT and implantation sites in BPH/5 mice at e7.5. Our data suggest a possible role for rWAT in the dyslipidemic state and inflammatory uterine milieu that might underlie the pathogenesis of PE. Future studies should further address the physiological functioning of the adipose tissue in relation to PE-related pregnancy outcomes.


Assuntos
Tecido Adiposo Branco/fisiologia , Tecido Adiposo/fisiologia , Dislipidemias/metabolismo , Pré-Eclâmpsia , Animais , Colesterol/biossíntese , Feminino , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos , Obesidade , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma
10.
Biochem Biophys Res Commun ; 510(3): 388-394, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30717975

RESUMO

The browning of white adipose tissue predominantly emerges as an adaptation to environmental cues, such as cold exposure. The enhanced browning of adipose tissue results in improved energy and glucose homeostasis and reduced fat mass and body weight, which is greatly beneficial for the treatment of obesity and other metabolic diseases. C1q/TNF-related protein 5 (CTRP5) is a novel adipokine associated with a variety of endocrine and metabolic diseases; however, whether it can regulate the metabolism of adipose tissue itself remains unknown. In this study, we demonstrated that the expression of CTRP5 in murine subcutaneous white adipose tissue (scWAT) was significantly decreased when the mice were exposed to cold temperatures. The lentivirus-mediated overexpression of CTRP5 in mice repressed the adipose tissue browning, leading to reduced heat production, decreased expression of the browning marker uncoupling protein 1 (UCP1) and decreased browning-related gene expression. Mechanistically, we found that autophagy was inhibited after cold exposure, but this inhibition was alleviated after CTRP5 overexpression. In primary cultured adipocytes, CTRP5 suppressed UCP1 expression, whereas 3-MA (an autophagy inhibitor) rescued the suppression. All of these results demonstrated that CTRP5 is a negative regulator of adipose browning. CTRP5 exerts its effect, at least in part, by suppressing adipocyte autophagy. Our findings indicated that CTRP5 is a novel promising therapeutic target for obesity and other metabolic diseases.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo Branco/metabolismo , Temperatura Baixa , Proteínas de Membrana/metabolismo , Adipócitos/fisiologia , Adipocinas/genética , Tecido Adiposo Branco/fisiologia , Animais , Autofagia , Células Cultivadas , Metabolismo Energético , Regulação da Expressão Gênica , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL
11.
Int J Sports Med ; 40(1): 57-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30497092

RESUMO

Exercise is recognized as an effective method to prevent obesity and alleviate metabolic diseases. Browning of white adipose has the advantage of decreasing insulin resistance. We aim to identify critical differentially expressed genes (DEGs) in white adipose tissue after exercise. We downloaded the gene dataset GSE68161 of C57BL/6 mice from the Gene Expression Omnibus (GEO) database. Then, we analyzed the effect of exercise on up-regulated and down-regulated DEGs by GEO2R and performed protein-protein interaction network analyses. We then identified hub-genes in white adipose tissue and crosstalk genes of a single pathway by the STRING database and Cytoscape. In this study, 72 DEGs were screened out, and they mainly function in glycerol-3-phosphate dehydrogenase activity and in the primary biological process of fatty acid oxidation regulation. The top 5 hub-genes screened out were SLC27A1, COX7A1, PPARGC1A, FABP3, and UCP1. The 3 crosstalk genes found were SLC27A1, SLC27A2, and PPARA. These 3 genes might function as a bridge of the PPAR signaling pathway, adipocytokine signaling pathway and the insulin resistance pathway. SLC27A1 is critical gene for the interactions of signaling pathways in subcutaneous white adipose tissue. Therefore, further relationships between the browning of white adipose and insulin resistance need to be studied.


Assuntos
Tecido Adiposo Branco/fisiologia , Exercício Físico/fisiologia , Mapas de Interação de Proteínas , Transcriptoma , Adipocinas/metabolismo , Animais , Mineração de Dados , Bases de Dados Genéticas , Regulação para Baixo , Humanos , Resistência à Insulina , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Transdução de Sinais , Regulação para Cima
12.
Artigo em Inglês | MEDLINE | ID: mdl-29800720

RESUMO

White adipocytes represent the principle site for energy storage whereas brown/beige adipocytes emerge from seemingly distinct cellular lineages and burn chemical energy to produce heat. Thermogenic adipocytes utilize cell-type selective master regulatory transcription factors to drive the expression of their adipocyte thermogenic gene program. White adipocytes harbor transcriptional mechanisms to suppress the thermogenic gene program and maintain an energy-storing function. Here, we summarize some of the key developmental and transcriptional mechanisms leading to the postnatal recruitment of thermogenic adipocytes under physiological conditions, with a particular emphasis on the transcriptional "brakes" on the thermogenic gene program. We highlight a number of recent studies, including our own work on the transcription factor, ZFP423, that illustrate the potential to engineer the subcutaneous and visceral white fat lineages to adopt a thermogenic fat cell fate by releasing the inhibition of the adipocyte thermogenic gene program. These transcriptional brakes on adipocyte thermogenesis may represent potential targets of therapeutic interventions designed to combat obesity and associated metabolic disorders.


Assuntos
Adipócitos/fisiologia , Termogênese , Tecido Adiposo Branco/fisiologia , Animais , Engenharia Genética , Humanos , Transcrição Genética
13.
Pflugers Arch ; 471(3): 455-465, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29982948

RESUMO

The need for effective and convenient ways of combatting obesity has created great interest in brown adipose tissue (BAT). However, because adult humans have relatively little amounts of BAT, the possibility of browning white adipose tissue (WAT), i.e., switching the metabolism of WAT from an energy storing to energy burning organ, has gained considerable attention. Exercise has countless health benefits, and has consistently been shown to cause browning in rodent white adipose tissue. The purpose of this review is to provide an overview of recent studies examining the effects of exercise and other interventions on the browning of white adipose tissue. The role of various endocrine factors, including catecholamines, interleukin-6, irisin, and meteorin-like in addition to local re-esterification-mediated mechanisms in inducing the browning of WAT will be discussed. The physiological importance of browning will be discussed, as will discrepancies in the literature between human and rodent studies.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Exercício Físico/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Metabolismo Energético/fisiologia , Humanos , Obesidade/fisiopatologia
14.
J Biochem ; 165(1): 47-55, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295852

RESUMO

Brown adipocytes play a critical role for adaptive thermogenesis to regulate body temperature in cold or to circumvent diet-induced obesity. In this study, we investigated the role of cellular repressor of E1A-stimulated genes 1 (CREG1) on brown adipogenesis and uncoupling protein 1 (UCP1) expression by using in vitro culture models. In murine mesenchymal stem cell line C3H10T1/2, Creg1 mRNA expression significantly increased in a time-dependent manner along with Ucp1 mRNA induction in brown adipogenesis. Creg1 gene overexpression upregulated the expression of brown fat-related genes including Ucp1 but its suppression downregulated these gene expression in C3H10T1/2 cells. Unlike the brown adipogenesis, Creg1 mRNA expression decreased significantly after differentiation stimulation in white adipogenesis of 3T3-L1 cells. Either Creg1 gene overexpression or suppression hardly affected white adipogenesis. In addition, CREG1 protein stimulated brown adipogenesis and rescued the adipogenesis in the absence of thyroid hormone in C3H10T1/2 cells. In reporter assay, CREG1 induction stimulated Ucp1 promoter activity, which was enhanced by co-expression with thyroid hormone receptors. The effect of CREG1 on Ucp1 promoter activity was also stimulated by retinoic acid. These results strongly suggest that CREG1 plays an important role on the regulation of UCP1 expression and brown adipogenesis.


Assuntos
Adipogenia/fisiologia , Tecido Adiposo Marrom/crescimento & desenvolvimento , Proteínas Repressoras/fisiologia , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Branco/fisiologia , Animais , Linhagem Celular , Regulação para Baixo , Regulação da Expressão Gênica/fisiologia , Camundongos Endogâmicos C3H , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/biossíntese , Termogênese , Hormônios Tireóideos/fisiologia , Tretinoína/farmacologia , Proteína Desacopladora 1/genética
15.
BMC Complement Altern Med ; 18(1): 323, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518367

RESUMO

BACKGROUND: Weight reduction frequently occurs in patients receiving vagus nerve stimulation (VNS) therapy. Therefore, we hypothesized that during dietary intervention for weight loss, auricular electric stimulation (AES), an alternative of VNS, accelerates weight loss by increasing white adipose tissue (WAT) browning and increases energy expenditure. METHODS: C57BL/6J male mice were fed a high-fat diet for 5 wk. to induce obesity, then switched to a low-fat diet for 5 wk. and allocated into 3 groups to receive 2 Hz electric stimulation on ears, electrode clamps only, or nothing (AES, Sham and Ctrl, respectively). RESULTS: Switching to a low-fat diet reduced body weight progressively in all 3 groups, with the greatest reduction in the AES group. In accordance with a mild decrease in feed intake, hypothalamus mRNA levels of Npy, AgRP tended to be reduced, while Pomc tended to be increased by AES. Mice in the AES group had the highest concentrations of norepinephrine in serum and inguinal WAT, and expression levels of uncoupling protein-1 (UCP-1) and tyrosine hydroxylase in inguinal WAT. Furthermore, their subcutaneous adipocytes had multilocular and UCP-1+ characteristics, along with a smaller cell size. CONCLUSION: AES, by increasing WAT browning, could be used in conjunction with a low-fat diet to augment weight loss in addition to suppressing appetite.


Assuntos
Tecido Adiposo Branco/fisiologia , Auriculoterapia/métodos , Dieta com Restrição de Gorduras , Estimulação Elétrica/métodos , Perda de Peso/fisiologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/terapia
16.
Nat Commun ; 9(1): 3622, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30190464

RESUMO

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans.


Assuntos
Tecido Adiposo Marrom/fisiologia , Impressão Genômica , Obesidade/genética , RNA Longo não Codificante/genética , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/etiologia
17.
Biol Sex Differ ; 9(1): 37, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157935

RESUMO

BACKGROUND: Recently, we have developed a novel transgenic mouse model by overexpressing prohibitin (PHB) in adipocytes, which developed obesity due to upregulation of mitochondrial biogenesis in adipocytes, hence named "Mito-Ob." Interestingly, only male Mito-Ob mice developed obesity-related impaired glucose homeostasis and insulin sensitivity, whereas female Mito-Ob mice did not. The observed sex differences in metabolic dysregulation suggest a potential involvement of sex steroids. Thus, the main aim of this study is to investigate the role of sex steroids on the overall phenotype of Mito-Ob mice through gonadectomy, as well as direct effect of sex steroids on adipocytes from Mito-Ob mice in vitro. METHODS: Mito-Ob mice and wild-type CD-1 mice were gonadectomized at 12 weeks of age. Age- and sex-matched sham-operated mice were used as controls. Body weight, white adipose tissue, glucose tolerance, and insulin sensitivity were analyzed 3 months post-surgery. Differentiation of adipocytes isolated from female and male Mito-Ob mice were studied with and without sex steroids. RESULTS: Gonadectomy significantly reduced body weight in Mito-Ob mice compared with sham-operated mice, whereas the opposite trend was observed in wild-type mice. These changes occurred independent of food intake. A corresponding decrease in adipose tissue weight was found in gonadectomized Mito-Ob mice, but depot-specific differences were observed in male and female. Gonadectomy improved glucose tolerance in male wild-type and Mito-Ob mice, but the effect was more pronounced in wild-type mice. Gonadectomy did not alter insulin sensitivity in male Mito-Ob mice, but it was improved in male wild-type mice. In primary cell cultures, testosterone inhibited adipocyte differentiation to a lesser extent in male Mito-Ob preadipocytes compared with the wild-type mice. On the other hand, preadipocytes from female wild-type mice showed better differentiation potential than those from female Mito-Ob mice in the presence of 17ß-estradiol. CONCLUSIONS: PHB requires sex steroids for the development of obese phenotype in Mito-Ob mice, which differentially affect glucose homeostasis and insulin sensitivity in male and female. It appears that PHB plays sex- and adipose depot-specific roles and involves additional factors. In vitro studies suggested that PHB differently influenced adipocyte differentiation in the presence and absence of sex steroids. Overall, this study along with available information in the literature indicated that a multifaceted relationship exists between PHB and sex steroids, which may work in a cell/tissue type- and sex-specific manner.


Assuntos
Tecido Adiposo Branco/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Proteínas Repressoras/fisiologia , Caracteres Sexuais , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo Branco/anatomia & histologia , Animais , Castração , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Obesidade/metabolismo , Tamanho do Órgão
18.
Nutrients ; 10(8)2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115853

RESUMO

The aim of this study was to determine whether the consumption of cherry out of its normal harvest photoperiod affects adipose tissue, increasing the risk of obesity. Fischer 344 rats were held over a long day (LD) or a short day (SD), fed a standard diet (STD), and treated with a cherry lyophilizate (CH) or vehicle (VH) (n = 6). Biometric measurements, serum parameters, gene expression in white (RWAT) and brown (BAT) adipose tissues, and RWAT histology were analysed. A second experiment with similar conditions was performed (n = 10) but with a cafeteria diet (CAF). In the STD experiment, Bmal1 and Cry1 were downregulated in the CHSD group compared to the VHSD group. Pparα expression was downregulated while Ucp1 levels were higher in the BAT of the CHSD group compared to the VHSD group. In the CAF-fed rats, glucose and insulin serum levels increased, and the expression levels of lipogenesis and lipolysis genes in RWAT were downregulated, while the adipocyte area increased and the number of adipocytes diminished in the CHSD group compared to the VHSD group. In conclusion, we show that the consumption of cherry out of season influences the metabolism of adipose tissue and promotes fat accumulation when accompanied by an obesogenic diet.


Assuntos
Tecido Adiposo Branco/fisiologia , Dieta , Frutas , Regulação da Expressão Gênica/efeitos dos fármacos , Prunus avium , Animais , Masculino , Fotoperíodo , Ratos , Ratos Endogâmicos F344 , Estações do Ano
19.
Mol Nutr Food Res ; 62(21): e1800463, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30095217

RESUMO

SCOPE: Resveratrol (RSV) and nicotinamide riboside (NR) are food compounds with anti-obesity actions in adult rodents. Here, the long-term effects of RSV and NR mild supplementation throughout lactation on adiposity-related parameters and the appearance of the beige phenotype in white adipose tissue (WAT) in adulthood are assessed. METHODS AND RESULTS: Newborn mice received orally RSV or NR from day 2 to 20 of life. Control littermates received the vehicle. All animals are weaned onto a chow diet on day 21. On day 90, half the animals of each group are assigned to a high-fat diet (HFD) for 10 weeks, while the other remained on a normal-fat diet. Energy-balance-related parameters, blood parameters, and gene expression and immunohistochemical analysis of WAT are assessed. Treated male mice show an improved response to the HFD, such as delayed body weight gain, a blunted increase in the plasma leptin/adiponectin ratio, and a decreased lipolytic response, together with signs of white-to-brown fat remodeling in inguinal WAT. These effects are absent in female mice. CONCLUSION: RSV and NR supplementations in early postnatal life affect WAT's thermogenic/oxidative transcriptional phenotype and metabolic responses in adulthood, with upregulatory and beneficial effects evidenced in male animals.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Niacinamida/análogos & derivados , Resveratrol/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lactação , Masculino , Camundongos Endogâmicos , Niacinamida/farmacologia , Fenótipo , Termogênese/efeitos dos fármacos , Termogênese/genética
20.
Exerc Sport Sci Rev ; 46(4): 232-239, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30001272

RESUMO

Reducing estrogen in women results in decreases in energy expenditure, but the mechanism(s) remain largely unknown. We postulate that the loss of estrogens in women is associated with increased accumulation of bone marrow-derived adipocytes in white adipose tissue, decreased activity of brown adipose tissue, and reduced levels of physical activity. Regular exercise may counteract the effects of estrogen deficiency.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Metabolismo Energético , Estrogênios/deficiência , Exercício Físico , Adipócitos/fisiologia , Animais , Feminino , Humanos , Menopausa
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