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1.
Sci Total Environ ; 730: 138652, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32416500

RESUMO

Air pollution was becoming a global threat to the public health, which was primarily mediated by PM2.5 induced cardiovascular diseases and pulmonary diseases. Recently, observational epidemiologic studies proposed the link between PM2.5 and obesity. Consistently, the link was also supported by limited animal researches. However, the potential mechanism mediating the harmful effects of PM2.5 was still elusive. In this study, we applied the "real-ambient exposure" system to conduct the experiments, which was closer to the status of ambient air pollution compared with the method of intratracheal instillation and concentrated air particles (CAPs) exposure system. Nuclear factor E2-related factor 2 (Nrf2) was previously reported to protect against inflammation and oxidative stress when exposed to PM2.5. Here, we reported that Nrf2-/- mice developed overgrowth of adipose tissue after "real-ambient exposure" to PM2.5, compared to filtered air (FA) group. Consistently, compared to FA group, adipocytes from subcutaneous (sWAT) and gonadal (gWAT) white adipose tissue of Nrf2-/- mice exhibited enlarged cell size in PM2.5 exposure group. Furthermore, the levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in serum and liver of Nrf2-/- mice were also altered statistically in PM2.5 exposure group. Importantly, when the expression of lipogenic enzymes was analyzed, the levels of the related specific genes in adipose tissue and liver of Nrf2-/- mice were altered in PM2.5 exposure group. Interestingly, the key transcription factors modulating expression of lipogenic enzymes in liver of Nrf2-/- mice were also found altered in PM2.5 exposure group, such as peroxisome proliferator-activated receptor (PPARα, PPARγ). Taken together, our study mimicked the status of ambient air pollution, revealed new insights into the adverse effect of PM2.5 exposure, provided new link between air pollution and overgrowth of adipose tissue, and supported the vital role of Nrf2 in mediating the side effects of PM2.5.


Assuntos
Poluição do Ar , Tecido Adiposo Branco , Poluentes Atmosféricos , Animais , Camundongos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Material Particulado
2.
PLoS One ; 15(5): e0227720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407314

RESUMO

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.


Assuntos
Dislipidemias/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Comportamento Animal/fisiologia , Relógios Circadianos/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Ácidos Graxos/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miofibrilas/patologia , Fotoperíodo
3.
PLoS Genet ; 16(5): e1008823, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453789

RESUMO

The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. However, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissue (WAT) development and protect mice from high-fat diet (HFD)-induced metabolic dysregulation. We found genetic polymorphisms in SLC2A10 locus are suggestively associated with a T2DM intermediate phenotype in non-diabetic Han Taiwanese. Additionally, mice carrying an orthologous human Glut10G128E variant (Glut10G128E mice) with compromised GLUT10 function have reduced adipogenesis, reduced WAT development and increased susceptibility to HFD-induced metabolic dysregulation. We further demonstrate that GLUT10 is highly expressed in preadipocytes, where it regulates intracellular ascorbic acid levels and adipogenesis. In this context, GLUT10 increases ascorbic acid-dependent DNA demethylation and the expression of key adipogenic genes, Cebpa and Pparg. Together, our data show GLUT10 regulates adipogenesis via ascorbic acid-dependent DNA demethylation to benefit proper WAT development and protect mice against HFD-induced metabolic dysregulation. Our findings suggest that SLC2A10 may be an important HFD-associated susceptibility locus for T2DM.


Assuntos
Tecido Adiposo Branco/metabolismo , Ácido Ascórbico/metabolismo , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Proteínas Facilitadoras de Transporte de Glucose/genética , Células 3T3-L1 , Adipogenia , Adulto , Idoso , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Metilação de DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação , PPAR gama/genética
4.
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
5.
Arch Biochem Biophys ; 686: 108364, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315653

RESUMO

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.


Assuntos
Suplementos Nutricionais/análise , Alga Marinha/química , Xantofilas/química , Xantofilas/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Descoberta de Drogas , Radicais Livres/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Resistência à Insulina , Fígado/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Oxigênio Singlete/metabolismo , Proteína Desacopladora 1/química , Proteína Desacopladora 1/metabolismo , Xantofilas/efeitos adversos , beta Caroteno/análogos & derivados , beta Caroteno/química
6.
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
7.
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
8.
Int J Sports Med ; 41(7): 427-442, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32252102

RESUMO

Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into "beige cells" that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.


Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Exercício Físico/fisiologia , Termogênese , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Biomarcadores/metabolismo , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Peptídeo Natriurético Encefálico/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína Desacopladora 1/metabolismo
9.
Clin Sci (Lond) ; 134(7): 921-939, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32239178

RESUMO

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Adiposidade , Dieta Hiperlipídica , Metabolismo Energético , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Adipócitos Brancos/patologia , Adipogenia/genética , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Tamanho Celular , Modelos Animais de Doenças , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica , Hipertrofia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos Endogâmicos C57BL , Estado Nutricional , Obesidade Materna/genética , Obesidade Materna/patologia , Obesidade Materna/fisiopatologia , Gravidez , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais , Fatores de Tempo
10.
Zhen Ci Yan Jiu ; 45(3): 251-4, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32202719

RESUMO

Acupuncture has become an effective approach in clinic for treating obesity, but its mechanism has not been clarified yet. A large number of researches have been conducted on the obesity mechanism in the aspects of neurophysiological regulation, feeding center regulation and peripheral digestion and absorption regulation at home and abroad. But, regarding the main storage site of excess energy, i.e. the remodeling and functional regulation of white adipose tissue (WAT), is still a new field in research. In the paper, focusing on the new filed of weight loss, in view of the promotion of WAT browning through the re-gulation of UCP1 and PPARγ signal pathway with acupuncture, the potential peripheral mechanism of acupuncture was explored on weight loss.


Assuntos
Terapia por Acupuntura , Tecido Adiposo Marrom , Tecido Adiposo Branco , Metabolismo Energético , Humanos , Obesidade
11.
Chemosphere ; 251: 126392, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32146191

RESUMO

Emerging evidence indicated that disruption of circadian rhythm (CR) induced metabolic disorders, including dysregulation of energy homeostasis and lipid dysfunction, which was associated with ambient fine particulate matter (PM2.5) as well. However, the role and mechanism of CR in PM2.5-mediated metabolic disorder remain unknown. In the present study, we investigated circadian rhythmic characteristics and explored the effect of PM2.5 on oscillating clock of lipid function and metabolism in white adipose tissue (WAT) and brown adipose tissue (BAT). C57BL/6 mice were exposed to PM2.5 in a whole-body inhalational exposure system. After 10 weeks, the expression of clock-related genes exhibits more robust CR in BAT than WAT, with the acrophase of PER2 in both types of adipose tissue being significantly decreased at ZT12 and Bmal1 increased at ZT0/24 in WAT in response to PM2.5 exposure. In addition, both CR pattern and expression levels of Sirt1 got significantly inhibited by PM2.5 exposure in WAT, accompanied with adipose dysfunction evidenced by inhibited pattern and expression levels of adipokines at the same ZT time points. Finally, a similar phase right shift from ZT4 to ZT12 in both Sirt3 and Ucp1 in BAT was induced by PM2.5 exposure. These findings indicate that disruption of the CR in adipose tissues could be an important way by which PM2.5 exposure induces metabolic disorder and provide potential targets for further investigation.


Assuntos
Tecido Adiposo/metabolismo , Ritmo Circadiano , Exposição por Inalação/efeitos adversos , Material Particulado/toxicidade , Tecido Adiposo Marrom , Tecido Adiposo Branco , Adiposidade , Animais , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Material Particulado/análise , Proteína Desacopladora 1
12.
Am J Physiol Endocrinol Metab ; 318(5): E600-E612, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32154743

RESUMO

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal day 21. We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Masculino , Exposição Materna , Camundongos , Gravidez , Fatores Sexuais , Estresse Fisiológico/fisiologia
13.
PLoS Biol ; 18(3): e3000688, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32218572

RESUMO

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fármacos Antiobesidade/uso terapêutico , Cumarínicos/uso terapêutico , Obesidade/prevenção & controle , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Reação de Maillard , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Propiltiouracila/toxicidade , Termogênese , Tri-Iodotironina/antagonistas & inibidores , Tri-Iodotironina/metabolismo , Ganho de Peso/efeitos dos fármacos
14.
Nat Commun ; 11(1): 624, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005798

RESUMO

Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Transdução de Sinais , Proteína Desacopladora 1/genética
15.
Life Sci ; 245: 117352, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32006527

RESUMO

AIMS: The depot-specific differences in lipidome of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reflect heterogeneity of white adipose tissue (WAT), which plays a central role in its distinct response to outside stimuli. However, the detailed lipidome of depot-specific WAT is largely unknown, especially the minor constitutes including phospholipid and sphingolipid. MATERIALS AND METHODS: To investigate this field, we applied a high-coverage targeted lipidomics approach of VAT and SAT in male C57BL/6J mice to compare the basal level of their lipid profiles. Applying microarray and quantitative real-time polymerase chain reaction, we analyzed the transcriptome of twodepot-specific WAT and verified the differences in individual genes. KEY FINDINGS: In total, 342 lipid species from 19 lipid classes were identified. Our results showed the composition of TAG and FFA were different in length of chain and saturation. Interestingly, low abundance phospholipid, sphingolipid and cardiolipin were significantly higher in SAT. Lipid correlation network analysis vindicated that TAG and phospholipid formed distinct subnet and had more connections with other lipid species. Enriched ontology analysis of gene screened from LIPID MAPS and microarray suggested the differences were mainly involved in lipid metabolism, insulin resistance and inflammatory response. SIGNIFICANCE: Our comprehensive lipidomics and transcriptomics analyses revealed differences in lipid composition and lipid metabolism of two depot-specific WAT, which would offer new insights into the investigation of heterogeneity of visceral and subcutaneous white adipose tissue.


Assuntos
Tecido Adiposo Branco/metabolismo , Gordura Intra-Abdominal/metabolismo , Lipidômica , Gordura Subcutânea/metabolismo , Transcriptoma , Tecido Adiposo Branco/química , Animais , Cardiolipinas/análise , Cardiolipinas/metabolismo , Ceramidas/análise , Ceramidas/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/metabolismo , Glicerídeos/análise , Glicerídeos/metabolismo , Gordura Intra-Abdominal/química , Metabolismo dos Lipídeos , Lipídeos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfolipídeos/análise , Fosfolipídeos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Gordura Subcutânea/química
16.
Life Sci ; 247: 117414, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035928

RESUMO

AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to significantly reduce body weight. This study investigated whether SGLT2 inhibitors directly affect adipose tissues and the underlying mechanisms in vivo and in vitro. MAIN METHODS: Male C57BL/6 mice were fed a normal diet, high-fat diet (HFD), or HFD with canagliflozin for 14 weeks. 3T3-L1 adipocytes were treated with canagliflozin. Metabolic parameters were measured. KEY FINDINGS: Canagliflozin reduced body weight, fat mass, and white adipose tissue (WAT) weight and inhibited adipocyte hypertrophy. Canagliflozin improved glucose and lipid metabolic disorders induced by HFD. Furthermore, canagliflozin treatment reversed the suppressed mRNA and protein expression of PGC-1α, NRF1, tfam and CPT1b, which are markers of mitochondrial biogenesis, function and fatty acid oxidation in mice with obesity. In vitro, canagliflozin increased mitochondrial DNA to nuclear DNA and upregulated the expression of PGC-1α, NRF1, tfam, COX5b, COX8b, Atp5o, and CPT1b mRNA and PGC-1α, NRF1, tfam, COX5b, CPT1b protein in 3T3-L1 adipocytes in a dose-dependent manner, while these increases were inhibited by GW6471, a PPARα antagonist. SIGNIFICANCE: Our study showed that canagliflozin protected against HFD-induced obesity and obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue and adipocytes. Such energy-dissipating effects of canagliflozin may be mediated by PPARα.


Assuntos
Canagliflozina/uso terapêutico , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , PPAR alfa/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Canagliflozina/farmacologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
17.
Biochem J ; 477(3): 583-600, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32026949

RESUMO

A central function of adipose tissue is in the management of systemic energy homeostasis that is achieved through the co-ordinated regulation of energy storage and mobilization, adipokine release, and immune functions. With the dramatic increase in the prevalence of obesity and obesity-related metabolic disease over the past 30 years, there has been extensive interest in targeting adipose tissue for therapeutic benefit. However, in order for this goal to be achieved it is essential to establish a comprehensive atlas of adipose tissue cellular composition and define mechanisms of intercellular communication that mediate pathologic and therapeutic responses. While traditional methods, such as fluorescence-activated cell sorting (FACS) and genetic lineage tracing, have greatly advanced the field, these approaches are inherently limited by the choice of markers and the ability to comprehensively identify and characterize dynamic interactions among stromal cells within the tissue microenvironment. Single cell RNA sequencing (scRNAseq) has emerged as a powerful tool for deconvolving cellular heterogeneity and holds promise for understanding the development and plasticity of adipose tissue under normal and pathological conditions. scRNAseq has recently been used to characterize adipose stem cell (ASC) populations and has provided new insights into subpopulations of macrophages that arise during anabolic and catabolic remodeling in white adipose tissue. The current review summarizes recent findings that use this technology to explore adipose tissue heterogeneity and plasticity.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco , Macrófagos/metabolismo , Células Estromais/citologia , Adipócitos/imunologia , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Comunicação Celular , Citometria de Fluxo , Humanos , Macrófagos/citologia , Obesidade/metabolismo , Obesidade/terapia , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/metabolismo , Células Estromais/patologia
18.
Am J Physiol Endocrinol Metab ; 318(5): E667-E677, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045263

RESUMO

The global prevalence of type 2 diabetes (T2D) has doubled since 1980. Human epidemiological studies support arsenic exposure as a risk factor for T2D, although the precise mechanism is unclear. We hypothesized that chronic arsenic ingestion alters glucose homeostasis by impairing adaptive thermogenesis, i.e., body heat production in cold environments. Arsenic is a pervasive environmental contaminant, with more than 200 million people worldwide currently exposed to arsenic-contaminated drinking water. Male C57BL/6J mice exposed to sodium arsenite in drinking water at 300 µg/L for 9 wk experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass and subcutaneous inguinal white adipose tissue (iWAT) mass. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting in WAT confirmed that arsenic significantly decreased TOMM20, a correlate of mitochondrial abundance; PGC1A, a master regulator of mitochondrial biogenesis; and, CPT1B, the rate-limiting step of fatty acid oxidation (FAO). Our findings show that chronic arsenic exposure impacts the mitochondrial proteins of thermogenic tissues involved in energy expenditure and substrate regulation, providing novel mechanistic evidence for arsenic's role in T2D development.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Arsenitos/farmacologia , Compostos de Sódio/farmacologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Metacrilatos , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores de Superfície Celular/metabolismo , Siloxanas , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
19.
Metabolism ; 105: 154169, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987858

RESUMO

BACKGROUND: Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. METHODS: Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. RESULTS: LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. CONCLUSIONS: Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.


Assuntos
Carcinoma Pulmonar de Lewis/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Músculo Esquelético/irrigação sanguínea , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/metabolismo , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Feminino , Intolerância à Glucose/complicações , Resistência à Insulina , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Músculo Esquelético/diagnóstico por imagem , Fluxo Sanguíneo Regional , Vasodilatadores/farmacologia
20.
Mol Cell ; 77(3): 600-617.e4, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31952989

RESUMO

Brown adipose tissue (BAT) is highly metabolically active tissue that dissipates energy via UCP1 as heat, and BAT mass is correlated negatively with obesity. The presence of BAT/BAT-like tissue in humans renders BAT as an attractive target against obesity and insulin resistance. Here, we identify Aifm2, a NADH oxidoreductase domain containing flavoprotein, as a lipid droplet (LD)-associated protein highly enriched in BAT. Aifm2 is induced by cold as well as by diet. Upon cold or ß-adrenergic stimulation, Aifm2 associates with the outer side of the mitochondrial inner membrane. As a unique BAT-specific first mammalian NDE (external NADH dehydrogenase)-like enzyme, Aifm2 oxidizes NADH to maintain high cytosolic NAD levels in supporting robust glycolysis and to transfer electrons to the electron transport chain (ETC) for fueling thermogenesis. Aifm2 in BAT and subcutaneous white adipose tissue (WAT) promotes oxygen consumption, uncoupled respiration, and heat production during cold- and diet-induced thermogenesis. Aifm2, thus, can ameliorate diet-induced obesity and insulin resistance.


Assuntos
Tecido Adiposo Marrom/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Mitocondriais/metabolismo , Termogênese/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Dieta , Metabolismo Energético , Glucose/metabolismo , Glicólise/fisiologia , Células HEK293 , Humanos , Resistência à Insulina , Gotículas Lipídicas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/fisiologia , Complexos Multienzimáticos/metabolismo , NAD/metabolismo , NAD/fisiologia , NADH NADPH Oxirredutases/metabolismo , Obesidade/metabolismo , Oxirredução , Consumo de Oxigênio , Proteína Desacopladora 1/metabolismo
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