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1.
Eur J Pharmacol ; 866: 172822, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31760068

RESUMO

Brown adipose tissue (BAT) plays important roles in regulating energy homeostasis and combating obesity. Accordingly, increasing the abundance and/or activating BAT would be effective and promising approaches to combat obesity and obesity-relative diseases. Our previous data in vitro have shown that osteopontin (OPN) induces the brown adipogenesis in 3T3-L1 cells via a phosphatidylinositol 3 kinase (PI3K)-AKT pathway. However, it is currently unknown whether OPN exerts such an effect on animals in vivo. Therefore, in the study we sought to investigate the pro-browning effects of OPN and to explore its underlying mechanisms by transfecting with Ad-GFP-aP2-OPN-shRNA to specifically down-regulate the OPN of white adipose tissue (WAT) in mice. Our present results show that downregulation of OPN in WAT exacerbates obesity and inhibits WAT-browning. Moreover, immunohistochemical results also exhibit that the downregulation of OPN significantly diminishes the expression and sub-cellular localization of UCP-1, PRDM16 and PGC-1α. Besides, the western blotting results reveal that the expression levels of PI3K, AKT-pS473 and PPARγ markedly reduce. Consequently, we conclude that the downregulation of OPN inhibits the browning of WAT through inhibiting the expression of PPARγ mediated by the PI3K-AKT pathway. The findings suggest that OPN is involved in regulation of WAT-browning and regulating its expression would become a potential strategy to combat obesity and obesity-relative metabolic diseases.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Regulação para Baixo , Osteopontina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células 3T3-L1 , Animais , Proteínas de Ligação a DNA/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/metabolismo
2.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640116

RESUMO

The growth of adipose tissue and its vasculature are tightly associated. Angiogenic factors have been linked to obesity, yet little is known about their expression during early childhood. To identify associations of angiogenic factors with characteristics on individual and tissue level, subcutaneous white adipose tissue samples were taken from 45 children aged 0-9 years undergoing elective surgery. We measured the expression of vascular endothelial growth factor A (VEFGA), fibroblast growth factor 1 and 2 (FGF1, FGF2), angiopoietin 1 and 2 (ANGPT1, ANGPT2), TEK receptor tyrosine kinase (TEK), and von Willebrand factor (VWF). In addition, we determined the mean adipocyte size in histologic tissue sections. We found positive correlations of age with FGF1 and FGF2 and a negative correlation with ANGPT2, with pronounced differences in the first two years of life. FGF1, FGF2, and ANGPT1 correlated positively with adipocyte size. Furthermore, we identified a correlation of ANGPT1 and TEK with body mass index-standard deviation score (BMI-SDS), a measure to define childhood obesity. Except for ANGPT2, all angiogenic factors correlated positively with the endothelial marker VWF. In sum, our findings suggest that differences related to BMI-SDS begin early in childhood, and the analyzed angiogenic factors possess distinct roles in adipose tissue biology.


Assuntos
Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Proteínas Angiogênicas/metabolismo , Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Índice de Massa Corporal , Tamanho Celular , Criança , Pré-Escolar , Feminino , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Receptor TIE-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de von Willebrand/metabolismo
3.
Eur J Pharmacol ; 863: 172708, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31568785

RESUMO

Obesity is a serious public health problem characterized by abnormal or excessive fat accumulation, which is caused by an energy imbalance between calories consumed and calories expended. MiRNAs have been involved in the regulation of occurrence and progression of obesity. This study aims to investigate the role of miR-324-5p in regulating the adipose tissue mass and preliminarily probe into its effect on progression of obesity. MiR-324-5p was upregulated in the epididymal white adipose tissues (eWAT), inguinal white adipose tissues (iWAT) and brown adipose tissues (BAT) of the mice fed with high fat diet (HFD). Under room temperature (RT) or thermoneutrality (TN) condition, when tail intravenously injected with miR-324-5p antagomir (anta-miR-324-5p), the fat mass and total weight of mice were both significantly suppressed. The suppressive effect was more distinct under TN than RT. The weight of iWAT and BAT were both inhibited by anta-miR-324-5p under TN. Moreover, PM20D1 was a direct target gene of miR-324-5p. In primary iWAT cells, the expression of PM20D1 was significantly increased by anta-miR-324-5p, whereas decreased by the miR-324-5p mimic. Furthermore, anta-miR-324-5p noticeably increased the cellular oxygen consumption in primary BAT and iWAT cells. Our findings indicated that inhibition of miR-324-5p increased PM20D1-mediated fat consumption and reduced body weight in mice, suggesting that miR-324-5p may be a novel therapeutic target against obesity.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Amidoidrolases/metabolismo , Peso Corporal/genética , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Amidoidrolases/genética , Animais , Antagomirs/genética , Progressão da Doença , Camundongos , Camundongos Endogâmicos BALB C , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Consumo de Oxigênio/genética , Termogênese/genética , Regulação para Cima/genética
4.
Diabetes ; 68(10): 1874-1885, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31540940

RESUMO

Activated beige adipocytes have therapeutic potential due to their ability to improve glucose and lipid homeostasis. To date, the origin of beige adipocytes remains enigmatic. Whether beige cells arise through de novo differentiation from resident precursors or through reprogramming of mature white adipocytes has been a topic of intense discussion. Here, we offer our perspective on the natural origin of beige adipocytes in mice. In particular, we revisit recent lineage-tracing studies that shed light on this issue and offer new insight into how environmental housing temperatures early in life influence the mode of beige adipocyte biogenesis upon cold exposure later in life. We suggest a unified model in which beige adipocytes (UCP1+ multilocular cells) in rodents initially arise predominantly from progenitors (i.e., de novo beige adipogenesis) upon the first exposure to cold temperatures and then interconvert between "dormant beige" and "active beige" phenotypes (i.e., beige cell activation) upon subsequent changes in environmental temperature. Importantly, we highlight experimental considerations needed to visualize de novo adipogenesis versus beige cell activation in mice. A precise understanding of the cellular origins of beige adipocytes emanating in response to physiological and pharmacological stimuli may better inform therapeutic strategies to recruit beige adipocytes in vivo.


Assuntos
Adipócitos Bege/citologia , Adipogenia/fisiologia , Tecido Adiposo Branco/citologia , Animais , Humanos , Termogênese/fisiologia
5.
Cells ; 8(7)2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262098

RESUMO

Obesity is characterized by chronic and low-grade systemic inflammation, an increase of adipose tissue, hypertrophy, and hyperplasia of adipocytes. Adipose tissues can be classified into white, brown, beige and pink adipose tissues, which display different regulatory, morphological and functional characteristics of their adipocyte and immune cells. Brown and white adipocytes can play a key role not only in the control of energy homeostasis, or through the balance between energy storage and expenditure, but also by the modulation of immune and inflammatory responses. Therefore, brown and white adipocytes can orchestrate important immunological crosstalk that may deeply impact the tumor microenvironment and be crucial for cancer establishment and progression. Recent works have indicated that white adipose tissues can undergo a process called browning, in which an inducible brown adipocyte develops. In this review, we depict the mechanisms involved in the differential role of brown, white and pink adipocytes, highlighting their structural, morphological, regulatory and functional characteristics and correlation with cancer predisposition, establishment, and progression. We also discuss the impact of the increased adiposity in the inflammatory and immunological modulation. Moreover, we focused on the plasticity of adipocytes, describing the molecules produced and secreted by those cells, the modulation of the signaling pathways involved in the browning phenomena of white adipose tissue and its impact on inflammation and cancer.


Assuntos
Adiposidade/imunologia , Carcinogênese/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Obesidade/imunologia , Adipócitos Marrons/imunologia , Adipócitos Marrons/metabolismo , Adipócitos Brancos/imunologia , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/imunologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Carcinogênese/patologia , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético/imunologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/complicações , Obesidade/metabolismo , Microambiente Tumoral/imunologia
6.
J Endocrinol ; 241(3): R97-R109, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31144796

RESUMO

In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true 'color', accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Obesidade/metabolismo , Termogênese , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Animais , Humanos , Camundongos , Modelos Biológicos
7.
Biosci Biotechnol Biochem ; 83(9): 1774-1781, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31130066

RESUMO

Previous studies including ours have shown that a low-protein diet up-regulates insulin signaling in the liver and muscle and induces fatty liver in rats. Adiponectin is known as an insulin-sensitizing adipocytokine. We, therefore, examined the effect of a low-protein diet on the adiponectin levels in rats. The low-protein diet significantly increased serum adiponectin level. However, mRNA and protein levels of adiponectin in white adipose tissue (WAT) were not changed by the low-protein diet. Since it is known that oligomerization is important to control serum adiponectin level, we examined the population of adiponectin oligomeric forms in WAT and found that low-protein diet did not change it. Despite these events, the amount of its secretion was significantly increased in the adipocytes isolated from WAT of low-protein diet-fed rats. These results indicate that a low-protein diet enhances adiponectin secretion, which is not due to the increased intracellular amount and oligomerization of adiponectin.


Assuntos
Adiponectina/metabolismo , Proteínas na Dieta/administração & dosagem , Adiponectina/genética , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Biopolímeros/metabolismo , Resistência à Insulina , Masculino , RNA Mensageiro/genética , Ratos , Ratos Wistar
8.
Nutrients ; 11(5)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064103

RESUMO

Nonalcoholic fatty liver diseases (NAFLD) is characterized by accumulation of lipid droplets in the liver. The objective of this study was to evaluate protective effects of fermented Cordyceps militaris extract by Pediococcus pentosaceus ON188 (ONE) against hepatosteatosis and obesity in mice fed a high-fat diet (HFD). Eight-week-old male C57BL/6J mice were fed HFD mixed with ONE for four weeks and its effects on hepatosteatosis and obesity were examined. Although ONE did not change food intake, it reduced body weights of mice at administration dose of 200 mg/kg/day. Activities of lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine transaminase (ALT) as plasma parameters were reduced by ONE in a dose-dependent manner. Hepatic lipid droplets and triglyceride (TG) levels were also reduced by ONE due to upregulation of fatty acid oxidizing genes such as carnithine palmitoyltransferase (CPT1) and peroxisomal proliferator activated receptor α(PPARα) mediated by induction of sphingosine kinase 2 (SPHK2). In epididymal fat tissue, sizes of adipocytes were significantly reduced by ONE in a dose-dependent manner. This is mainly due to suppression of lipogenesis and upregulation of adipocyte browning genes. Collectively, these results suggest that fermented ONE can activate fatty acid oxidation via SPHK2 in the liver. It can also suppress lipogenesis and activate browning in adipose tissue. Thus, ONE might have potential to be used for the development of functional foods against liver dysfunction and obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Cordyceps/química , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Adenosina/química , Tecido Adiposo Branco/citologia , Animais , Produtos Biológicos/química , Desoxiadenosinas/química , Fígado Gorduroso/induzido quimicamente , Fermentação , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regulação para Cima
9.
J Clin Invest ; 129(6): 2485-2499, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31081799

RESUMO

Prevalence of obesity among infants and children below 5 years of age is rising dramatically, and early childhood obesity is a forerunner of obesity and obesity-associated diseases in adulthood. Childhood obesity is hence one of the most serious public health challenges today. Here, we have identified a mother-to-child lipid signaling that protects from obesity. We have found that breast milk-specific lipid species, so-called alkylglycerol-type (AKG-type) ether lipids, which are absent from infant formula and adult-type diets, maintain beige adipose tissue (BeAT) in the infant and impede the transformation of BeAT into lipid-storing white adipose tissue (WAT). Breast milk AKGs are metabolized by adipose tissue macrophages (ATMs) to platelet-activating factor (PAF), which ultimately activates IL-6/STAT3 signaling in adipocytes and triggers BeAT development in the infant. Accordingly, lack of AKG intake in infancy leads to a premature loss of BeAT and increases fat accumulation. AKG signaling is specific for infants and is inactivated in adulthood. However, in obese adipose tissue, ATMs regain their ability to metabolize AKGs, which reduces obesity. In summary, AKGs are specific lipid signals of breast milk that are essential for healthy adipose tissue development.


Assuntos
Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Glicerídeos/metabolismo , Macrófagos/metabolismo , Leite Humano/metabolismo , Adipócitos Bege/citologia , Tecido Adiposo Branco/citologia , Animais , Feminino , Glicerídeos/genética , Humanos , Lactente , Interleucina-6/genética , Interleucina-6/metabolismo , Macaca mulatta , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
10.
J Invest Dermatol ; 139(5): 1002-1009, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30879642

RESUMO

Dermal white adipose tissue is a unique layer of adipocytes within the reticular dermis of the skin. Recently, several nonmetabolic activities have been discovered for dWAT and its fibroblast precursors. These functions include antimicrobial defense and roles in hair cycling, wound healing, and thermogenesis. In this review, we discuss recent progress in understanding the role of dermal white adipose tissue in immunity, both as an innate antimicrobial cell type and as an indirect communicator with other cutaneous immunocytes to enhance defense and potentially contribute to inflammatory disease.


Assuntos
Tecido Adiposo Branco/imunologia , Imunidade Inata/fisiologia , Cicatrização/imunologia , Ferimentos e Lesões/imunologia , Tecido Adiposo Branco/citologia , Animais , Derme/imunologia , Derme/metabolismo , Feminino , Humanos , Masculino , Sensibilidade e Especificidade , Pele/imunologia , Pele/metabolismo , Cicatrização/fisiologia , Ferimentos e Lesões/metabolismo
11.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1451-1459, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797958

RESUMO

Browning of white adipose tissues (WAT) is critical for a variety of physiological and pathophysiological events. Given the limited understanding in molecular control of WAT browning, further research is needed. Heat shock protein A12A (HSPA12A) is a new member of multigene Hsp70 family. This study investigated the effect of HSPA12A on the browning of WAT. WAT Browning in mice was induced by cold exposure for 5 days. We observed that nuclear HSPA12A content was increased in WAT after cold exposure, while deficiency of HSPA12A (Hspa12a-/-) promoted the cold-induced browning of WAT in mice compared to wild type (WT) littermates. Accordingly, Hspa12a-/- mice showed attenuation of body temperature drop and increase of thermogenic gene expression compared to WT mice after cold exposure. However, in vitro experiments demonstrated that HSPA12A deficiency in primary white adipocytes did not affect their browning and thermogenic gene expression. Further loss- and gain-of-HSPA12A functional studies revealed that HSPA12A deficiency promoted whereas HSPA12A overexpression impeded M2 macrophage polarization. Importantly, the conditioned medium (CM) from Hspa12a-/- bone marrow-derived macrophages (BMDMs) enhanced the browning of primary white adipocytes when compared to the CM from WT BMDMs. The data identified macrophage HSPA12A as a novel regulator of WAT browning through a paracrine mechanism. Targeting HSPA12A might provide meaningful advances for the management of browning-associated physiological events such as hypothermia adaptation and pathophysiological disorders such as obesity and cancer-related cachexia.


Assuntos
Adaptação Fisiológica/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético/genética , Proteínas de Choque Térmico HSP70/genética , Macrófagos/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Animais , Temperatura Corporal , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Temperatura Baixa , Meios de Cultivo Condicionados/farmacologia , Expressão Gênica , Proteínas de Choque Térmico HSP70/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Comunicação Parácrina/genética , Cultura Primária de Células , Células RAW 264.7
12.
Phytomedicine ; 52: 254-263, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599906

RESUMO

BACKGROUND: Platycodi Radix (root of Platycodon grandiflorum) and its active compound platycodin D (PD) has been previously shown to possess anti-obesity properties, but the underlying mechanisms remain poorly understood. PURPOSE: The present study was aimed to evaluate the anti-obese effect of PD and reveal its mechanism of action. STUDY DESIGN/METHODS: Genetically obese db/db mice were orally treated with PD for 4 weeks, and body weight gain, adipose tissue weight, serum parameters were measured. Then, assays on adipogenic factors, thermogenic factors, and AMP-activated protein kinase (AMPK) pathway were performed in PD-treated 3T3-L1 murine adipocytes, human adipose-derived mesenchymal stem cells (hAMSCs), and primary cultured brown adipocytes. RESULTS: PD treatment attenuated body weight gain, suppressed white adipose tissue weight and improved obesity-related serum parameters in db/db mice. Two major adipogenic factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) were decreased by PD treatment in WAT of db/db mice, 3T3-L1 adipocytes and hAMSCs. In BAT of db/db mice and primary cultured brown adipocytes, PD treatment elevated the expressions of uncoupled protein 1 (UCP1) and peroxisome proliferator-activated receptor γ coactivator 1 α (PCG1α), the key regulators of BAT-associated thermogenesis. In addition, PD activated AMPKα both in vivo and in vitro. However, when AMPK was inhibited by compound C, PD treatment failed to suppress adipogenic factors and increase thermogenic factors. CONCLUSIONS: PD improved obesity in db/db mice by AMPK-associated decrease of adipogenic markers including PPARγ and C/EBPα. PD increased thermogenic factors such as UCP1 and PGC1α in db/db mice and primary cultured brown adipocytes. AMPK inhibition nullified the effects of PD, suggesting its anti-adipogenic and thermogenic actions were dependent on AMPK pathway activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Obesidade/tratamento farmacológico , Saponinas/farmacologia , Termogênese/efeitos dos fármacos , Triterpenos/farmacologia , Células 3T3-L1 , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Knockout , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Platycodon/química , Proteína Desacopladora 1/metabolismo
13.
FASEB J ; 33(4): 5196-5207, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30624970

RESUMO

Bone marrow provides progenitors of several types of cells, including muscle and white adipocytes, ensuring peripheral tissue homeostasis. However, the role of bone marrow-derived cells (BMCs) in induction of thermogenic adipocytes is unresolved. The purpose of this study is to examine whether BMCs are involved in the emergence of thermogenic adipocytes through adrenergic activation. Irradiation of mice with 8 Gy of X-ray-depleted BMCs and peripheral blood mononucleated cells (PBMCs), which in turn impaired induction of uncoupling protein 1 (UCP1) through administration of ß3 adrenergic receptor agonist, CL 316,243 (CL), in inguinal white adipose tissue (iWAT). In contrast, CL-induced UCP1 induction in brown adipose tissue was unaffected by BMC depletion. Transplantation of normal BMCs into mice depleted of BMCs recovered PBMC levels and rescued the ability of iWAT browning by CL. Furthermore, analyses of mice transplanted with green fluorescent protein (GFP)-labeled BMCs revealed that the number of GFP-positive BMCs and PBMCs were significantly decreased by CL and that GFP-positive stromal cells and GFP-positive UCP1-expressing multilocular adipocytes appeared in iWAT after CL administration, demonstrating differentiation of BMC-derived preadipocytes into UCP1-expressing thermogenic adipocytes. These results unveiled a crucial role of the BMC as a nonresident origin for a subset of thermogenic adipocytes, contributing to browning of white adipose tissue.-Yoneshiro, T., Shin, W., Machida, K., Fukano, K., Tsubota, A., Chen, Y., Yasui, H., Inanami, O., Okamatsu-Ogura, Y., Kimura, K. Differentiation of bone marrow-derived cells toward thermogenic adipocytes in white adipose tissue induced by the ß3 adrenergic stimulation.


Assuntos
Adipócitos/citologia , Tecido Adiposo Branco/citologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/fisiologia , Receptores Adrenérgicos beta 3/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Western Blotting , Transplante de Medula Óssea , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Citometria de Fluxo , Imunofluorescência , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 1/metabolismo
14.
Mol Cell Biochem ; 450(1-2): 65-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29808464

RESUMO

White adipose tissue (WAT) is the bulk of fatty tissues in humans. Enhancing the potential of WAT-derived stem cells (WATDCs) to generate cardiomyocytes may help supply sufficient number of therapeutically potent cells for heart repair in vivo. Therefore, we investigated whether ascorbic acid (AA) could facilitate the cardiac differentiation of WATDCs and the underlying mechanisms. Our results indicated that AA dose-dependently stimulates the cardiac differentiation of WATDCs, which is supported by the up-regulated expression of cardiac markers and the appearance of myotube-like cell morphologies. Time-course study showed that the front phase (0-4 days) is crucial for the action of AA on cardiac differentiation, which hints that AA may take effect through enhancing the proliferation of cardiac progenitor cells. EdU assay ascertained AA indeed promotes cell growth dose-dependently in the front phase. Further investigation indicated that AA induces the phosphorylation of MEK and ERK, and the synthesis of collagen I (Col I). Interference of MEK/ERK activity or Col I synthesis blocks the cardiomyogenic activity of AA in WATDCs. These findings demonstrated that AA facilitates WATDC cardiogenesis via promoting the proliferation of cardiac progenitor cells through MEK/ERK signaling and collagen synthesis.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Ácido Ascórbico/farmacologia , Diferenciação Celular/efeitos dos fármacos , Miócitos Cardíacos/citologia , Organogênese , Células-Tronco/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Antioxidantes/farmacologia , Proliferação de Células , Células Cultivadas , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
15.
Methods Mol Biol ; 1896: 31-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30474837

RESUMO

Senescence-associated ß-galactosidase (hereafter SA-ß-gal) staining has now been employed for more than 20 years to identify the presence of senescent cells (Dimri et al., Proc Natl Acad Sci U S A 92:9363-9367, 1995). These cells, characterized by a permanent cell-cycle arrest (Hayflick and Moorhead, Exp Cell Res 25:585-621, 1961) and the production of a distinct secretory phenotype of cytokines, chemokines, and proteases (Coppe et al., PLoS Biol 6:2853-2868, 2008), have received much attention in recent years for their impacts on diverse biological processes. Here we describe a method to identify and quantify the specific cells that become senescent in vivo using transmission electron microscopy after SA-ß-gal staining that can be used in countless scenarios.


Assuntos
Tecido Adiposo Branco/enzimologia , Aterosclerose/enzimologia , Senescência Celular , Túbulos Renais/enzimologia , Pericárdio/enzimologia , beta-Galactosidase/metabolismo , Tecido Adiposo Branco/citologia , Animais , Aterosclerose/patologia , Células Cultivadas , Túbulos Renais/citologia , Camundongos , Pericárdio/citologia
16.
Trends Endocrinol Metab ; 30(2): 93-105, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30558832

RESUMO

Hair follicles (HFs) strongly interact with adipocytes within the dermal white adipose tissue (dWAT), suggesting a strong physiological dependence on the content of immature and mature adipocytes in this layer. This content is regulated by the proliferation and differentiation of adipocyte precursors, as well as by dedifferentiation of mature existing adipocytes. Spatially, long-range interactions between HFs and dWAT involve the exchange of extracellular vesicles which are differentially released by precursors, preadipocytes, and mature adipocytes. Different exogenous factors, including light irradiation, are likely to modify the release of adipocyte-derived exosomes in dWAT, which can lead to aberrations of the HF cycle. Consequently, dWAT should be considered as a potential target for the modulation of hair growth.


Assuntos
Tecido Adiposo Branco/citologia , Folículo Piloso/citologia , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Folículo Piloso/metabolismo , Humanos
17.
Nature ; 565(7738): 180-185, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568302

RESUMO

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of ß-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival.


Assuntos
Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/metabolismo , Temperatura Baixa , Resposta ao Choque Frio , Glicólise , Desenvolvimento Muscular , Aclimatação , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular , Sobrevivência Celular , Metabolismo Energético , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Homeostase , Masculino , Camundongos , Proteína MyoD/metabolismo , Mioblastos/citologia , Receptores Adrenérgicos beta/metabolismo
18.
J Vis Exp ; (141)2018 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-30507917

RESUMO

Adipose tissue is an important metabolic organ with high plasticity and is responsive to environmental stimuli and nutrient status. As such, various techniques have been developed to study the morphology and biology of adipose tissue. However, conventional visualization methods are limited to studying the tissue in 2D sections, failing to capture the 3D architecture of the whole organ. Here we present whole-mount staining, an immunohistochemistry method that preserves intact adipose tissue morphology with minimal processing steps. Hence, the structures of adipocytes and other cellular components are maintained without distortion, achieving the most representative 3D visualization of the tissue. In addition, whole-mount staining can be combined with lineage tracing methods to determine cell fate decisions. However, this technique has some limitations to providing accurate information regarding deeper parts of adipose tissue. To overcome this limitation, whole-mount staining can be further combined with tissue clearing techniques to remove the opaqueness of tissue and allow for complete visualization of entire adipose tissue anatomy using light-sheet fluorescent microscopy. Therefore, a higher resolution and more accurate representation of adipose tissue structures can be captured with the combination of these techniques.


Assuntos
Tecido Adiposo Branco/química , Tecido Adiposo Branco/citologia , Imageamento Tridimensional/métodos , Coloração e Rotulagem/métodos , Tecido Adiposo/química , Tecido Adiposo/citologia , Animais , Imuno-Histoquímica , Microscopia de Fluorescência/métodos
19.
Cell Physiol Biochem ; 51(6): 2900-2915, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562744

RESUMO

BACKGROUND/AIMS: Brown and beige adipocytes are widely recognized as potential therapeutic targets to treat obesity and related metabolic disorders, and the recruitment of brown and beige adipocytes is an essential aspect that requires attention. Although many methods of activating brown adipocytes or generating beige adipocytes have been reported, the limited number and sources are the biggest challenges. The number of white adipocytes is much greater than the number of brown adipocytes, both in human adults and fetuses. Unfortunately, human adult white adipose tissue-derived stem cell (aWAsc) has little beige adipogenic potential. However, the characteristics and beige adipogenic potential of human embryo-derived white adipose stem cells (eWAsc) still need to be investigated. METHODS: To analyze the characteristics and functionality of eWAsc, we analyzed the markers of adipose precursor cells by flow cytometry. Then, differentiation and browning/beiging were induced, and the identifying markers were analyzed by real-time PCR and immunoblot. In addition, more in-depth exploration was performed using RNA-SEQ on eWAsc and aWAsc. RESULTS: eWAsc was isolated from human embryonic white adipose tissue, and aWAsc was isolated from adult white adipose tissue by collagenase treatment. eWAsc has extreme advantages in adipogenesis capacity and browning/beiging ability in comparison to aWAsc, indicating that eWAsc may possess some special regulatory factors to promote the generation of functional brown/beige adipocytes. Greater exploration was enabled by RNA-SEQ, revealing a large number of differences at the transcriptional levels, including 1263 differentially expressed genes, 657 down- and 605 upregulated, in eWAsc compared to aWAsc. Pathway analysis revealed enrichment in cell cycle, TGF-ß signaling pathway, DNA replication, and Hippo signaling pathways. Interestingly, the expression levels of C/EBPα, FGF1 and FST gene, which are related to the maturation of adipocytes, Hippo signaling pathway and TGF-ß signaling pathway, were significantly higher in eWAsc than in aWAsc. These may be potential candidates and possible regulatory targets for recruiting beige adipocytes in human adipose tissue. CONCLUSION: Overall, we have demonstrated the molecular characteristics and excellent beige adipogenic potential of eWAsc, providing a new reference for studying human adipocytes.


Assuntos
Adipogenia , Tecido Adiposo Bege/citologia , Tecido Adiposo Branco/citologia , Embrião de Mamíferos/citologia , Células-Tronco/citologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Células Cultivadas , Embrião de Mamíferos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco/metabolismo
20.
BMC Genomics ; 19(1): 794, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390616

RESUMO

BACKGROUND: Norepinephrine (NE) signaling has a key role in white adipose tissue (WAT) functions, including lipolysis, free fatty acid liberation and, under certain conditions, conversion of white into brite (brown-in-white) adipocytes. However, acute effects of NE stimulation have not been described at the transcriptional network level. RESULTS: We used RNA-seq to uncover a broad transcriptional response. The inference of protein-protein and protein-DNA interaction networks allowed us to identify a set of immediate-early genes (IEGs) with high betweenness, validating our approach and suggesting a hierarchical control of transcriptional regulation. In addition, we identified a transcriptional regulatory network with IEGs as master regulators, including HSF1 and NFIL3 as novel NE-induced IEG candidates. Moreover, a functional enrichment analysis and gene clustering into functional modules suggest a crosstalk between metabolic, signaling, and immune responses. CONCLUSIONS: Altogether, our network biology approach explores for the first time the immediate-early systems level response of human adipocytes to acute sympathetic activation, thereby providing a first network basis of early cell fate programs and crosstalks between metabolic and transcriptional networks required for proper WAT function.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/citologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genes Precoces , Norepinefrina/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas , Anotação de Sequência Molecular , Norepinefrina/farmacologia , Transdução de Sinais , Transcrição Genética , Transcriptoma
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