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1.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502211

RESUMO

Obesity is a condition characterized by uncontrolled expansion of adipose tissue mass resulting in pathological weight gain. Histone deacetylases (HDACs) have emerged as crucial players in epigenetic regulation of adipocyte metabolism. Previously, we demonstrated that selective inhibition of class I HDACs improves white adipocyte functionality and promotes the browning phenotype of murine mesenchymal stem cells (MSCs) C3H/10T1/2 differentiated to adipocytes. These effects were also observed in db/db and diet induced obesity mouse models and in mice with adipose-selective inactivation of HDAC3, a member of class I HDACs. The molecular basis of class I HDACs action in adipose tissue is not deeply characterized and it is not known whether the effects of their inhibition are exerted on adipocyte precursors or mature adipocytes. Therefore, the aim of the present work was to explore the molecular mechanism of class I HDAC action in adipocytes by evaluating the effects of HDAC3-specific silencing at different stages of differentiation. HDAC3 was silenced in C3H/10T1/2 MSCs at different stages of differentiation to adipocytes. shRNA targeting HDAC3 was used to generate the knock-down model. Proper HDAC3 silencing was assessed by measuring both mRNA and protein levels of mouse HDAC3 via qPCR and western blot, respectively. Mitochondrial DNA content and gene expression were quantified via qPCR. HDAC3 silencing at the beginning of differentiation enhanced adipocyte functionality by amplifying the expression of genes regulating differentiation, oxidative metabolism, browning and mitochondrial activity, starting from 72 h after induction of differentiation and silencing. Insulin signaling was enhanced as demonstrated by increased AKT phosphorylation following HDAC3 silencing. Mitochondrial content/density did not change, while the increased expression of the transcriptional co-activator Ppargc1b suggests the observed phenotype was related to enhanced mitochondrial activity, which was confirmed by increased maximal respiration and proton leak linked to reduced coupling efficiency. Moreover, the expression of pro-inflammatory markers increased with HDAC3 early silencing. To the contrary, no differences in terms of gene expression were found when HDAC3 silencing occurred in terminally differentiated adipocyte. Our data demonstrated that early epigenetic events mediated by class I HDAC inhibition/silencing are crucial to commit adipocyte precursors towards the above-mentioned metabolic phenotype. Moreover, our data suggest that these effects are exerted on adipocyte precursors.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Diferenciação Celular , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Mitocôndrias/metabolismo , Fenótipo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Animais , Histona Desacetilases/genética , Camundongos , Camundongos Endogâmicos C3H
2.
Nat Commun ; 12(1): 5274, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489410

RESUMO

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.


Assuntos
Tecido Adiposo Marrom/fisiologia , Temperatura Corporal/fisiologia , Proteínas Morfogenéticas Ósseas/sangue , Peso ao Nascer , Glicemia/análise , Temperatura Baixa , Fatores de Crescimento de Fibroblastos/sangue , Hormônios/sangue , Humanos , Recém-Nascido , Termogênese/fisiologia
3.
Nat Commun ; 12(1): 5255, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489438

RESUMO

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.


Assuntos
Tecido Adiposo Marrom/citologia , Monócitos/fisiologia , Adiponectina/genética , Tecido Adiposo Marrom/fisiologia , Animais , Diferenciação Celular/genética , Contagem de Leucócitos , Macrófagos/citologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos Transgênicos , Monócitos/citologia , Tomografia por Emissão de Pósitrons , Receptores CCR2/genética , Receptores CCR2/metabolismo
4.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072788

RESUMO

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.


Assuntos
Tecido Adiposo/embriologia , Tecido Adiposo/fisiologia , Termogênese , Adipócitos/metabolismo , Adipogenia , Tecido Adiposo Bege/fisiologia , Tecido Adiposo Marrom/fisiologia , Envelhecimento/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia , Redes e Vias Metabólicas , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/terapia , Organogênese , Termogênese/efeitos dos fármacos , Termogênese/fisiologia
5.
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33944778

RESUMO

Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.


Assuntos
Tecido Adiposo Marrom/fisiologia , Aminoácidos de Cadeia Ramificada/metabolismo , Febre/fisiopatologia , Proteínas Mitocondriais/metabolismo , Termogênese/genética , Adaptação Fisiológica , Aminoácidos de Cadeia Ramificada/genética , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Proteínas Mitocondriais/genética , Ratos
6.
Am J Physiol Endocrinol Metab ; 321(1): E47-E62, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33969705

RESUMO

Myoglobin (Mb) regulates O2 bioavailability in muscle and heart as the partial pressure of O2 (Po2) drops with increased tissue workload. Globin proteins also modulate cellular NO pools, "scavenging" NO at higher Po2 and converting NO2- to NO as Po2 falls. Myoglobin binding of fatty acids may also signal a role in fat metabolism. Interestingly, Mb is expressed in brown adipose tissue (BAT), but its function is unknown. Herein, we present a new conceptual model that proposes links between BAT thermogenic activation, concurrently reduced Po2, and NO pools regulated by deoxy/oxy-globin toggling and xanthine oxidoreductase (XOR). We describe the effect of Mb knockout (Mb-/-) on BAT phenotype [lipid droplets, mitochondrial markers uncoupling protein 1 (UCP1) and cytochrome C oxidase 4 (Cox4), transcriptomics] in male and female mice fed a high-fat diet (HFD, 45% of energy, ∼13 wk), and examine Mb expression during brown adipocyte differentiation. Interscapular BAT weights did not differ by genotype, but there was a higher prevalence of mid-large sized droplets in Mb-/-. COX4 protein expression was significantly reduced in Mb-/- BAT, and a suite of metabolic/NO/stress/hypoxia transcripts were lower. All of these Mb-/--associated differences were most apparent in females. The new conceptual model, and results derived from Mb-/- mice, suggest a role for Mb in BAT metabolic regulation, in part through sexually dimorphic systems and NO signaling. This possibility requires further validation in light of significant mouse-to-mouse variability of BAT Mb mRNA and protein abundances in wild-type mice and lower expression relative to muscle and heart.NEW & NOTEWORTHY Myoglobin confers the distinct red color to muscle and heart, serving as an oxygen-binding protein in oxidative fibers. Less attention has been paid to brown fat, a thermogenic tissue that also expresses myoglobin. In a mouse knockout model lacking myoglobin, brown fat had larger fat droplets and lower markers of mitochondrial oxidative metabolism, especially in females. Gene expression patterns suggest a role for myoglobin as an oxygen/nitric oxide-sensor that regulates cellular metabolic and signaling pathways.


Assuntos
Tecido Adiposo Marrom/fisiologia , Mioglobina/fisiologia , Adipócitos Marrons/fisiologia , Tecido Adiposo Marrom/química , Tecido Adiposo Marrom/ultraestrutura , Animais , Diferenciação Celular , Células Cultivadas , Dieta Hiperlipídica , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Expressão Gênica , Lipídeos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Mioglobina/deficiência , Mioglobina/genética , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , RNA Mensageiro/análise
7.
Nat Metab ; 3(4): 485-495, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33846638

RESUMO

Brown adipose tissue (BAT) and beige fat function in energy expenditure in part due to their role in thermoregulation, making these tissues attractive targets for treating obesity and metabolic disorders. While prolonged cold exposure promotes de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we identify transient receptor potential cation channel subfamily V member 1 (Trpv1)+ vascular smooth muscle (VSM) cells as previously unidentified thermogenic adipocyte progenitors. Single-cell RNA sequencing analysis of interscapular brown adipose depots reveals, in addition to the previously known platelet-derived growth factor receptor (Pdgfr)α-expressing mesenchymal progenitors, a population of VSM-derived adipocyte progenitor cells (VSM-APC) expressing the temperature-sensitive cation channel Trpv1. We demonstrate that cold exposure induces the proliferation of Trpv1+ VSM-APCs and enahnces their differentiation to highly thermogenic adipocytes. Together, these findings illustrate the landscape of the thermogenic adipose niche at single-cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.


Assuntos
Adipócitos/fisiologia , Temperatura Baixa , Células-Tronco Hematopoéticas/fisiologia , Músculo Liso Vascular/fisiologia , Canais de Cátion TRPV/fisiologia , Termogênese/fisiologia , Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/fisiologia , Animais , Regulação da Temperatura Corporal/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Canais de Cátion TRPV/genética
8.
Nat Metab ; 3(4): 469-484, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33846639

RESUMO

Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we determine the identity of perivascular adipocyte progenitors in mice and humans. In mice, thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra+, Ly6a+ and Pparg-) and preadipocytes (Pdgfra+, Ly6a+ and Pparg+), which share transcriptional similarity with analogous cell types in white adipose tissue. Interestingly, the aortic adventitia of adult animals contains a population of adipogenic smooth muscle cells (Myh11+, Pdgfra- and Pparg+) that contribute to perivascular adipocyte formation. Similarly, human PVAT contains presumptive fibroblastic and smooth muscle-like adipocyte progenitor cells, as revealed by single-nucleus RNA sequencing. Together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity.


Assuntos
Adipócitos Marrons/fisiologia , Tecido Adiposo Marrom/fisiologia , Linhagem da Célula/fisiologia , Termogênese/fisiologia , Adipócitos Brancos/fisiologia , Adipogenia/fisiologia , Tecido Adiposo Marrom/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Aorta/citologia , Aorta/fisiologia , Vasos Sanguíneos/fisiologia , Linhagem da Célula/genética , Fibroblastos/fisiologia , Regulação da Expressão Gênica/fisiologia , Humanos , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/fisiologia , Células-Tronco/fisiologia , Termogênese/genética
9.
Immunol Cell Biol ; 99(7): 749-766, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33866598

RESUMO

Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high-fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPCs)-which give rise to DCs-in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the 'whitening' effect of eating a high-fat diet upon interscapular (i) BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPCs and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional DCs (cDCs) increased in both of these tissues. When compared with a low-fat diet, consumption of a high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed the high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin [blocked using the scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO)], but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction .


Assuntos
Tecido Adiposo Marrom , Células-Tronco Hematopoéticas , Tecido Adiposo Marrom/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Células Progenitoras Mieloides , Raios Ultravioleta
10.
J Endocrinol ; 249(3): 223-237, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33877054

RESUMO

Estrogen receptor ß (ERb), one of the two major estrogen receptors, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study assessed the effect of ERb classical genomic activity on adipocyte-specific and -systemic metabolic responses to wheel running exercise in a rodent model of menopause. Female mice lacking the ERb DNA-binding domain (ERbDBDKO, n = 20) and WT (n = 21) littermate controls were fed a high-fat diet (HFD), ovariectomized (OVX), and randomized to control (no running wheel) and exercise (running wheel access) groups and were followed for 8 weeks. Wheel running did not confer protection against metabolic dysfunction associated with HFD+OVX in either ERbDBDKO or WT mice, despite increased energy expenditure. Unexpectedly, in the ERbDBDKO group, wheel running increased fasting insulin and surrogate measures of insulin resistance, and modestly increased adipose tissue inflammatory gene expression (P ≤ 0.05). These changes were not accompanied by significant changes in adipocyte mitochondrial respiration. It was demonstrated for the first time that female WT OVX mice do experience exercise-induced browning of white adipose tissue, indicated by a robust increase in uncoupling protein 1 (UCP1) (P ≤ 0.05). However, KO mice were completely resistant to this effect, indicating that full ERb genomic activity is required for exercise-induced browning. The inability to upregulate UCP1 with exercise following OVX may have resulted in the increased insulin resistance observed in KO mice, a hypothesis requiring further investigation.


Assuntos
Receptor beta de Estrogênio/metabolismo , Atividade Motora/fisiologia , Ovariectomia , Adipócitos/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Dieta Hiperlipídica , Metabolismo Energético , Receptor beta de Estrogênio/genética , Feminino , Regulação da Expressão Gênica , Genótipo , Glucose/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout
11.
Nat Metab ; 3(4): 496-512, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33859430

RESUMO

Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.


Assuntos
Adipócitos/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Tecido Adiposo Marrom/fisiologia , Animais , Quinase 5 Dependente de Ciclina/metabolismo , Dieta , Dieta Hiperlipídica , Digoxina/farmacologia , Metabolismo Energético/fisiologia , Fezes/química , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Hipernutrição , PPAR gama/metabolismo , Fosforilação , Termogênese/fisiologia
12.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805982

RESUMO

Adipose tissue and its crosstalk with other organs plays an essential role in the metabolic homeostasis of the entire body. Alteration of this communication (i.e., due to obesity) is related to the development of several comorbidities including type 2 diabetes, cardiovascular diseases, or cancer. Within the adipose depot, adipocytes are the main cell type and thus the main source of secreted molecules, which exert modulating effects not only at a local but also at a systemic level. Extracellular vesicles (EVs) have recently emerged as important mediators in cell-cell communication and account for part of the cellular secretome. In recent years, there has been a growing body of research on adipocyte-derived extracellular vesicles (Ad-EVs). However, there is still a lack of standardized methodological approaches, especially regarding primary adipocytes. In this review, we will provide an outline of crucial aspects when working on adipose-derived material, with a special focus on primary adipocytes. In parallel, we will point out current methodological challenges in the EV field and how they impact the transcriptomic, proteomic and functional evaluations of Ad-EVs.


Assuntos
Adipócitos/citologia , Tecido Adiposo/fisiologia , Comunicação Celular , Tecido Adiposo Marrom/fisiologia , Animais , Células Cultivadas , Comorbidade , Vesículas Extracelulares/metabolismo , Humanos , Camundongos , Obesidade/metabolismo , Proteômica , Reprodutibilidade dos Testes , Células-Tronco/citologia , Transcriptoma
13.
Nutrients ; 13(5)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923364

RESUMO

Pediatric obesity remains a challenge in modern society. Recently, research has focused on the role of the brown adipose tissue (BAT) as a potential target of intervention. In this review, we revised preclinical and clinical works on factors that may promote BAT or browning of white adipose tissue (WAT) from fetal age to adolescence. Maternal lifestyle, type of breastfeeding and healthy microbiota can affect the thermogenic activity of BAT. Environmental factors such as exposure to cold or physical activity also play a role in promoting and activating BAT. Most of the evidence is preclinical, although in clinic there is some evidence on the role of omega-3 PUFAs (EPA and DHA) supplementation on BAT activation. Clinical studies are needed to dissect the early factors and their modulation to allow proper BAT development and functions and to prevent onset of childhood obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Dieta/métodos , Microbioma Gastrointestinal , Obesidade Pediátrica/prevenção & controle , Animais , Aleitamento Materno , Humanos , Alimentos Infantis , Camundongos , Prebióticos , Probióticos
14.
Sci Rep ; 11(1): 6526, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753827

RESUMO

This exploratory retrospective study aims to investigate the thermal changes in the thyroid gland region of patients with hypothyroidism and fibromyalgia by analyzing the temperature of the brown adipose tissue (BAT). A total of 166 individuals from 1000 thermographic electronic medical records were classified into four groups: Group HP + FM-50 individuals with hypothyroidism and fibromyalgia; Group FM-56 individuals with fibromyalgia only; Group HP-30 individuals with hypothyroidism only, and Group Control-30 healthy individuals. The thermal images from the electronic medical records were acquired by a FLIR T650SC infrared camera (used for thermometry) and the temperature data for each group were statistically analyzed. Group HP + FM showed r = 0, meaning that the average temperatures of the thyroid and BAT are independent of each other. Groups FM, HP and Control showed r = 1, meaning that the average temperatures of the thyroid and BAT were directly related. Our findings showed that the average temperatures of the thyroid and BAT regions are similar. Also, there was no correlation between thyroid gland temperature and the presence of hypothyroidism or fibromyalgia using thermometry.


Assuntos
Tecido Adiposo Marrom/fisiologia , Fibromialgia/fisiopatologia , Hipotireoidismo/fisiopatologia , Glândula Tireoide/fisiopatologia , Tecido Adiposo Marrom/diagnóstico por imagem , Adolescente , Adulto , Registros Eletrônicos de Saúde , Feminino , Fibromialgia/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Hipotireoidismo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Temperatura , Termografia/métodos , Glândula Tireoide/diagnóstico por imagem , Adulto Jovem
15.
Eur J Endocrinol ; 184(6): R243-R259, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33729178

RESUMO

Excessive accumulation of white adipose tissue leads to obesity and its associated metabolic health consequences such as type 2 diabetes and cardiovascular disease. Several approaches to treat or prevent obesity including public health interventions, surgical weight loss, and pharmacological approaches to reduce caloric intake have failed to substantially modify the increasing prevalence of obesity. The (re-)discovery of active brown adipose tissue (BAT) in adult humans approximately 15 years ago led to a resurgence in research into whether BAT activation could be a novel therapy for the treatment of obesity. Upon cold stimulus, BAT activates and generates heat to maintain body temperature, thus increasing energy expenditure. Activation of BAT may provide a unique opportunity to increase energy expenditure without the need for exercise. However, much of the underlying mechanisms surrounding BAT activation are still being elucidated and the effectiveness of BAT as a therapeutic target has not been realised. Research is ongoing to determine how best to expand BAT mass and activate existing BAT; approaches include cold exposure, pharmacological stimulation using sympathomimetics, browning agents that induce formation of thermogenic beige adipocytes in white adipose depots, and the identification of factors secreted by BAT with therapeutic potential. In this review, we discuss the caloric capacity and other metabolic benefits from BAT activation in humans and the role of metabolic tissues such as skeletal muscle in increasing energy expenditure. We discuss the potential of current approaches and the challenges of BAT activation as a novel strategy to treat obesity and metabolic disorders.


Assuntos
Tecido Adiposo Marrom/fisiologia , Regulação da Temperatura Corporal , Obesidade/fisiopatologia , Metabolismo Energético , Humanos , Obesidade/terapia
16.
J Clin Endocrinol Metab ; 106(5): 1437-1447, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33524145

RESUMO

CONTEXT: Elevating nicotinamide adenine dinucleotide (NAD+) levels systemically improves metabolic health, which can be accomplished via nicotinamide riboside (NR). Previously, it was demonstrated that NR supplementation in high-fat-diet (HFD)-fed mice decreased weight gain, normalized glucose metabolism, and enhanced cold tolerance. OBJECTIVE: Because brown adipose tissue (BAT) is a major source of thermogenesis, we hypothesize that NR stimulates BAT in mice and humans. DESIGN AND INTERVENTION: HFD-fed C56BL/6J mice were supplemented with 400 mg/kg/day NR for 4 weeks and subsequently exposed to cold. In vitro primary adipocytes derived from human BAT biopsies were pretreated with 50 µM or 500 µM NR before measuring mitochondrial uncoupling. Human volunteers (45-65 years; body mass index, 27-35 kg/m2) were supplemented with 1000 mg/day NR for 6 weeks to determine whether BAT activity increased, as measured by [18F]FDG uptake via positron emission tomography-computed tomography (randomized, double blinded, placebo-controlled, crossover study with NR supplementation). RESULTS: NR supplementation in HFD-fed mice decreased adipocyte cell size in BAT. Cold exposure further decreased adipocyte cell size on top of that achieved by NR alone independent of ex vivo lipolysis. In adipocytes derived from human BAT, NR enhanced in vitro norepinephrine-stimulated mitochondrial uncoupling. However, NR supplementation in human volunteers did not alter BAT activity or cold-induced thermogenesis. CONCLUSIONS: NR stimulates in vitro human BAT but not in vivo BAT in humans. Our research demonstrates the need for further translational research to better understand the differences in NAD+ metabolism in mouse and human.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Piridínio/farmacologia , Receptores Adrenérgicos/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Adrenérgicos/farmacologia , Idoso , Animais , Células Cultivadas , Estudos Cross-Over , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Niacinamida/farmacologia , Cultura Primária de Células , Termogênese/efeitos dos fármacos
17.
Biochem Biophys Res Commun ; 547: 29-35, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33592376

RESUMO

Brown adipose tissue (BAT) and stimulating adaptive thermogenesis have been implicated as anti-obese and anti-diabetic tissues due to their ability to dissipate energy as heat by the expression of UCP1. We have recently demonstrated that TRB3 impairs differentiation of brown preadipocytes via inhibiting insulin signaling. However, the roles of the protein in BAT function and thermogenesis in vivo have not yet been established. For this study we tested the hypothesis that TRB3 mediates obesity- and diabetes-induced impairments in BAT differentiation and function, and that inhibition of TRB3 improves BAT function. TRB3 expression was increased in BAT from high-fat fed mice and ob/ob mice, which was associated with decreased UCP1 expression. Incubation of brown adipocytes with palmitate increased TRB3 expression and decreased UCP1. Knockout of TRB3 in mice displayed higher UCP1 expression in BAT and cold resistance. Incubation of brown adipocytes with ER stressors increased TRB3 but decreased UCP1 and ER stress markers were elevated in BAT from high-fat fed mice and ob/ob mice. Finally, high-fat feeding in TRB3KO mice were protected from obesity-induced glucose intolerance and displayed cold resistance and higher expression of BAT-specific markers. These data demonstrate that high-fat feeding and obesity increase TRB3 in BAT, resulting in impaired tissue function.


Assuntos
Tecido Adiposo Marrom/metabolismo , Proteínas de Ciclo Celular/metabolismo , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/fisiologia , Animais , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/patologia , Transdução de Sinais , Termogênese
18.
Nat Commun ; 12(1): 843, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594062

RESUMO

Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33-/- mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-ß-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.


Assuntos
MicroRNAs/metabolismo , Sistema Nervoso Simpático/fisiologia , Termogênese/genética , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Corporal/fisiologia , Peso Corporal , Encéfalo/metabolismo , Linhagem Celular , Temperatura Baixa , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Humanos , Integrases/metabolismo , Masculino , Camundongos , Camundongos Obesos , MicroRNAs/genética , Consumo de Oxigênio/fisiologia , Fenótipo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
19.
Am J Physiol Endocrinol Metab ; 320(3): E488-E495, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459179

RESUMO

Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy expenditure. Some interventions such as cold and ß-adrenergic drugs are able to activate BAT thermogenesis as well as promote differentiation of white adipocytes into brown-like cells (browning), enhancing the thermogenic activity of these cells. In this mini-review, we discuss new mechanisms related to BAT and energy expenditure. In this regard, we will also discuss recent studies that have revealed the existence of important secretory molecules from BAT "batokines" that act in autocrine, paracrine, and endocrine mechanisms, which in turn may explain some of the beneficial roles of BAT on whole body glucose and fat metabolism. Finally, we will discuss new insights related to BAT thermogenesis with an additional focus on the distinct features of BAT metabolism between rodents and humans.


Assuntos
Tecido Adiposo Marrom/fisiologia , Adipócitos Brancos/metabolismo , Animais , Metabolismo Energético/fisiologia , Glucose/metabolismo , Humanos , Termogênese/fisiologia
20.
Cell Death Dis ; 12(1): 134, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510128

RESUMO

Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.


Assuntos
Tecido Adiposo Marrom/fisiologia , Caquexia/fisiopatologia , Vesículas Extracelulares/patologia , Lipólise/fisiologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Animais , Carcinoma Pulmonar de Lewis , Diferenciação Celular , Humanos , Masculino , Camundongos
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