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1.
PLoS Comput Biol ; 16(8): e1008044, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797044

RESUMO

Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, ßsubq = 0.45; Pvisc = 2.5 × 10-55, ßvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.


Assuntos
Adipócitos , Aprendizado de Máquina , Obesidade , Adipócitos/classificação , Adipócitos/citologia , Tecido Adiposo/fisiologia , Adulto , Índice de Massa Corporal , Tamanho Celular , Biologia Computacional/métodos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Obesidade/epidemiologia , Obesidade/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
2.
PLoS One ; 15(8): e0237095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756599

RESUMO

Regular exercise is an effective strategy that is used to prevent and treat obesity as well as type 2 diabetes. Exercise-induced myokine secretion is considered a mechanism that coordinates communication between muscles and other organs. In order to examine the possibility of novel communications from muscle to adipose tissue mediated by myokines, we treated 3T3-L1 adipocytes with C2C12 myotube electrical pulse stimulation-conditioned media (EPS-CM), using a C2C12 myotube contraction system stimulated by an electrical pulse. Continuous treatment with myotube EPS-CM promoted adipogenesis of 3T3-L1 pre-adipocytes via the upregulation of the peroxisome proliferator-activated receptor-gamma (PPARγ) 2 and PPARγ-regulated gene expression. Furthermore, our results revealed that myotube EPS-CM induces lipolysis and secretion of adiponectin in mature adipocytes. EPS-CM obtained from a C2C12 myoblast culture did not induce such changes in these genes, suggesting that contraction-induced myokine(s) secretion occurs particularly in differentiated myotubes. Thus, contraction-induced secretion of myokine(s) promotes adipogenesis and lipid metabolism in 3T3-L1 adipocytes. These findings suggest the possibility that skeletal muscle communicates to adipose tissues during exercise, probably by the intermediary of unidentified myokines.


Assuntos
Adipócitos/citologia , Diferenciação Celular , Lipólise , Fibras Musculares Esqueléticas/metabolismo , Células 3T3 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia , Adiponectina/metabolismo , Animais , Comunicação Celular , Meios de Cultivo Condicionados/farmacologia , Camundongos , PPAR gama/metabolismo
3.
PLoS One ; 15(7): e0236069, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692763

RESUMO

Adipocytes are derived from pluripotent mesenchymal stem cells through adipogenesis. Pre-adipocyte differentiation in poultry greatly influences fat deposition and meat quality. Circular RNAs (circRNAs) have an important function in cancer and some differentiation processes. Herein, high-throughput transcriptome sequencing was used to detect circRNAs present in cherry valley duck pre-adipocyte and adipocyte differentiation over 3 days. We identified 9,311 circRNAs and 141 differentially expressed circRNAs. Sequencing results were verified through qRT-PCR using seven randomly selected circRNAs, and competing endogenous RNA (ceRNA) networks were exhibited by ten important circRNAs in duck adipocyte differentiation. circRNA plexin A1 (circ-PLXNA1) was detected in duck adipocytes and mainly expressed in adipose, leg muscle and liver. Inhibition of circ-PLXNA1 limited the differentiation of duck adipocyte. There were four corresponding miRNAs for circ-PLXNA1 and 313 target genes for those miRNAs. CeRNA"circ-PLXNA1/miR-214/CTNNB1 axis" was focused and verified by a dual-luciferase reporter experiment. After co-transfection of cells with si-circ-PLXNA1 and miR-214 mimics, the expression level of CTNNB1 was down-regulated, triglyceride content and the adipogenic capacity of preadipocytes decreased. While there were no significant change after si-CTNNB1 transfection. All these results provide further insight into the circRNAs, especially for circ-PLXNA1 in duck adipocyte differentiation.


Assuntos
Adipócitos/citologia , Diferenciação Celular/genética , Patos , Perfilação da Expressão Gênica , RNA Circular/sangue , RNA Circular/genética , Animais , MicroRNAs/genética
4.
PLoS One ; 15(7): e0236286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702004

RESUMO

Functional brown adipose tissue (BAT) was identified in adult humans only in 2007 with the use of fluorodeoxyglucose positron emission tomography imaging. Previous studies have demonstrated a negative correlation between obesity and BAT presence in humans. It is proposed that BAT possesses the capacity to increase metabolism and aid weight loss. In rodents it is well established that BAT is stimulated by the sympathetic nervous system with the interscapular BAT being innervated via branches of intercostal nerves. Whilst there is evidence to suggest that BAT possesses beta-3 adrenoceptors, no studies have identified the specific nerve branch that carries sympathetic innervation to BAT in humans. The aim of this study was to identify and trace the peripheral nerve or nerves that innervate human BAT in the supraclavicular region. The posterior triangle region of the neck of cadaveric specimens were dissected in order to identify any peripheral nerve branches piercing and/or terminating in supraclavicular BAT. A previously undescribed branch of the cervical plexus terminating in a supraclavicular adipose depot was identified in all specimens. This was typically an independent branch of the plexus, from the third cervical spinal nerve, but in one specimen was a branch of the supraclavicular nerve. Histological analysis revealed the supraclavicular adipose depot contained tyrosine hydroxylase immunoreactive structures, which likely represent sympathetic axons. This is the first study that identifies a nerve branch to supraclavicular BAT-like tissue. This finding opens new avenues for the investigation of neural regulation of fat metabolism in humans.


Assuntos
Tecido Adiposo/inervação , Clavícula/inervação , Adipócitos/citologia , Tecido Adiposo/anatomia & histologia , Idoso , Cadáver , Forma Celular , Clavícula/anatomia & histologia , Dissecação , Humanos , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Nat Commun ; 11(1): 2797, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493999

RESUMO

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
6.
Nat Commun ; 11(1): 2995, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532984

RESUMO

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. Adipocyte function is regulated by receptor-mediated activation of heterotrimeric G proteins. Little is known about the potential in vivo metabolic roles of Gi-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this question, we generated mice lacking functional Gi proteins selectively in adipocytes. Here we report that these mutant mice displayed significantly impaired glucose tolerance and reduced insulin sensitivity when maintained on an obesogenic diet. In contrast, using a chemogenetic strategy, we demonstrated that activation of Gi signaling selectively in adipocytes greatly improved glucose homeostasis and insulin signaling. We also elucidated the cellular mechanisms underlying the observed metabolic phenotypes. Our data support the concept that adipocyte Gi signaling is essential for maintaining euglycemia. Drug-mediated activation of adipocyte Gi signaling may prove beneficial for restoring proper glucose homeostasis in type 2 diabetes.


Assuntos
Adipócitos/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Resistência à Insulina/genética , Transdução de Sinais/genética , Adipócitos/citologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Perfilação da Expressão Gênica/métodos , Intolerância à Glucose/genética , Homeostase/genética , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Obesidade/sangue , Obesidade/genética , Obesidade/metabolismo
7.
Mol Cell Endocrinol ; 515: 110917, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32593740

RESUMO

Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication. RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above. Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes. The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization. Our results, in human subcutaneous adipocytes cell culture, indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of COVID-19 infection as therapeutic strategy to decrease ACE2 regulatory genes.


Assuntos
Adipócitos/efeitos dos fármacos , Fibronectinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Betacoronavirus/genética , Betacoronavirus/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Infecções por Coronavirus/virologia , Fibronectinas/genética , Fibronectinas/metabolismo , Furina/genética , Furina/metabolismo , Ontologia Genética , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Biológicos , Anotação de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Obesidade/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Proteínas rab1 de Ligação ao GTP/genética , Proteínas rab1 de Ligação ao GTP/metabolismo
8.
Inflamm Res ; 69(9): 825-839, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32529477

RESUMO

PURPOSE: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. RESULTS: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.


Assuntos
Envelhecimento , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/virologia , Inflamação/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Adipócitos/citologia , Fatores Etários , Idoso , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Autofagia , Betacoronavirus , Senescência Celular , Citocinas/imunologia , Humanos , Sistema Imunitário , Inflamação/fisiopatologia , Pandemias , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Vitamina D/metabolismo , Deficiência de Vitamina D
9.
Phytomedicine ; 71: 153225, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32464299

RESUMO

BACKGROUND: Impaired bone formation is one of the reasons behind osteoporosis. Alterations in the patterns of mesenchymal stromal cell differentiation towards adipocytes instead of osteoblasts contribute to osteoporosis progression. Natural anti-osteoporotic agents are effective and safe alternatives for osteoporosis treatment. PURPOSE: In this context, 3,5-dicaffeoyl­epi-quinic acid (DCEQA) which is a derivative of chlorogenic acid with reported bioactivities was studied for its osteogenic differentiation enhancing potential in vitro. METHODS: Anti-osteoporotic effects of DCEQA were investigated in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) which were induced to differentiate into osteoblasts or adipocytes with or without DCEQA treatment. Changes in the osteogenic and adipogenic markers such as ALP activity and lipid accumulation, respectively, were observed along with differentiation-specific activation of mitogen activated protein kinase (MAPK) pathways. RESULTS: At 10 µM concentration, DCEQA increased the proliferation of bone marrow-derived human mesenchymal stromal cells (hBM-MSCs) during osteoblast differentiation. The expression of osteogenic markers ALP, osteocalcin, Runx2, BMP2 and Wnt 10a was upregulated by DCEQA treatment. The ALP activity and extracellular mineralization were also increased. DCEQA elevated the phosphorylation levels of p38 and JNK MAPKs as well as the activation of ß-catenin and Smad1/5. DCEQA suppressed the lipid accumulation and downregulated expression of adipogenic markers PPARγ, C/EBPα and SREBP1c in adipo-induced hBM-MSCs. DCEQA also decreased the phosphorylation of p38 and ERK MAPKs and stimulated the activation of AMPK in hBM-MSC adipocytes. CONCLUSION: DCEQA was suggested to enhance osteoblast differentiation via stimulating Wnt/BMP signaling. The adipocyte differentiation inhibitory effect of DCEQA was suggested to arise from its ability to increase AMPK phosphorylation. Overall, DCEQA was shown to possess osteogenesis enhancing and adipogenesis inhibitory properties which might facilitate its use against osteoporotic conditions.


Assuntos
Adipócitos/citologia , Atriplex/química , Ácido Clorogênico/análogos & derivados , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Células da Medula Óssea , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ácido Clorogênico/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
10.
Mol Biol (Mosk) ; 54(2): 233-243, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392192

RESUMO

Obesity is a major disease that causes significant complications. Inhibition of preadipocyte proliferation has the potential to prevent obesity and metabolic diseases. Melatonin is a pineal gland hormone that has various effects on cells and tissues. In this research, we investigated whether melatonin induces apoptosis in 3T3-L1 preadipocytes. 3T3-L1 preadipocytes were cultured until confluence and then treated with 0, 10, 100, and 1000 µM melatonin for 1, 3, and 5 days. A cell viability assay kit was used for determining cell viability. Cell death marker proteins were assessed by Western blot analysis using GAPDH for control. Apoptotic morphological changes with nuclei fragmentation were observed using DAPI staining. Melatonin treatment decreased the phosphorylated extracellular signal-regulated kinases (p-ERK) activation while increasing the activation of caspase-3, 8, and 9. Furthermore, melatonin not only increased Bcl-2-associated X protein (Bax) but decreased B-cell lymphoma 2 (Bcl-2) expression as dose increases from 0 to 1000 µM. The melatonin treatment also suppressed the growth of preadipocytes with increasing concentration. These effects were attenuated by luzindole, a melatonin receptor antagonist and U0126, an inhibitor of p-ERK activation. In conclusion, melatonin can induce apoptosis of 3T3-L1 preadipocytes via p-ERK decrease.


Assuntos
Adipócitos/citologia , Apoptose , Melatonina/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Caspases/metabolismo , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
11.
Proc Natl Acad Sci U S A ; 117(22): 12359-12367, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404422

RESUMO

Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is caused by reduced hepatocyte growth factor activation and impaired Met signaling, resulting in decreased liver glucose and lipid metabolism and enhanced adipocyte browning. Hepsin-deficient mice exhibit marked resistance to high-fat diet-induced obesity, hyperglycemia, and hyperlipidemia. In db/db mice, hepsin deficiency ameliorates obesity and diabetes. These data indicate that hepsin is a key regulator in liver metabolism and energy homeostasis, suggesting that hepsin could be a therapeutic target for treating obesity and diabetes.


Assuntos
Adipócitos/metabolismo , Fígado/metabolismo , Obesidade/enzimologia , Serina Endopeptidases/metabolismo , Adipócitos/citologia , Animais , Diferenciação Celular , Glucose/metabolismo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Serina Endopeptidases/genética
12.
Hum Cell ; 33(3): 502-511, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32447572

RESUMO

Antipsychotic-induced weight gain is a well-established but poorly understood clinical phenomenon. New mechanistic insights into how antipsychotics modulate adipose physiology are sorely needed, in hopes of either devising a therapeutic intervention to ameliorate weight gain or contributing to improved design of future agents. In this study, we have hypothesized that the weight gain-associated tricyclic antipsychotics clozapine and chlorpromazine directly impact adipose tissue by potentiating adipogenic differentiation of preadipocytes. Utilizing a well-established in vitro model system (3T3-L1 preadipocyte cell line), we demonstrate that, when applied specifically during induction of adipogenic differentiation, both clozapine and chlorpromazine significantly potentiate in vitro adipogenesis, observed as morphological changes and increased intracellular lipid accumulation. These persistent effects, observed at endpoints well after the end of antipsychotic exposure, are accompanied by increased transcript- and protein-level expression of the mature adipocyte marker perilipin-1, as indicated by RT-qPCR and Western blotting, but not by further upregulation of pro-adipogenic transcription factors versus positive controls. Our findings point to a possible physiological mechanism of antipsychotic-induced hyperplasia, with potentiated expression of mature adipocyte markers enhancing the differentiation and maturation of preadipocytes.


Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Antidepressivos Tricíclicos/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Células Cultivadas , Humanos , Ganho de Peso/efeitos dos fármacos
13.
Obes Facts ; 13(2): 221-236, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32252061

RESUMO

OBJECTIVES: To investigate the impact of omentin on the release of inflammation-related biomarkers and inflammatory pathways in primary human adipocytes. METHODS: Adipocytes were treated with or without omentin (500 and 2,000 ng/mL), and the supernatants were analyzed for inflammation-related biomarkers using proximity extension assay technology. Potential upstream regulators of the omentin-stimulated proteins were identified using Ingenuity Pathway Analysis. Protein levels of components of inflammatory pathways were measured using Western blotting. RESULTS: 2,000 ng/mL omentin induced the release of 30 biomarkers 97.1 ± 31.1-fold in the supernatants (all p < 0.05). Most biomarkers were proin-flammatory chemokines and cytokines. We identified the transcription factor nuclear factor "kappa-light-chain-enhancer" of activated B cells (NFĸB) and the kinases p38 and extracellular signal-regulated kinase (ERK)1/2 as potential upstream regulators in silico. On the cellular level, treatment with 2,000 ng/mL omentin for 24 h enhanced the phosphorylation levels of NFĸB 2.1 ± 0.3-fold (p < 0.05), of p38 2.6 ± 0.4-fold (p < 0.05), and of ERK1/2 1.8 ± 0.2-fold (p < 0.05). CONCLUSIONS: These data argue that omentin exerts proinflammatory effects through the activation of the inflammatory NFĸB, p38, and ERK1/2 pathways in cultured primary adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Citocinas/farmacologia , Mediadores da Inflamação/metabolismo , Lectinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Adipócitos/citologia , Células Cultivadas , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/farmacologia , Humanos , NF-kappa B/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Life Sci ; 248: 117474, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112869

RESUMO

BACKGROUND/OBJECTIVES: Nicotinamide N-methyltransferase (NNMT) is a novel regulator of energy homeostasis in adipocytes. NNMT expression in adipose tissue is increased in obesity and diabetes. Knockdown of NNMT prevents mice from developing diet-induced obesity, which is closely linked to insulin resistance. An early sign of systemic insulin resistance is reduced expression of glucose transporter 4 (GLUT4) selectively in adipose tissue. Adipose tissue-specific knockout and overexpression of GLUT4 cause reciprocal changes in NNMT expression. The aim of the current study was to elucidate the mechanism that regulates NNMT expression in adipocytes. METHODS: 3T3-L1 adipocytes were cultured in media with varying glucose concentrations or activators and inhibitors of intracellular pathways. NNMT mRNA and protein levels were measured with quantitative polymerase chain reaction and Western blotting. RESULTS: Glucose deprivation of 3T3-L1 adipocytes induced a 2-fold increase in NNMT mRNA and protein expression. This effect was mimicked by inhibition of glucose transport with phloretin, and by inhibition of glycolysis with the phosphoglucose isomerase inhibitor 2-deoxyglucose. Conversely, inhibition of the pentose phosphate pathway did not affect NNMT expression. Pharmacological activation of the cellular energy sensor AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin (mTOR) pathway caused an increase in NNMT levels that was similar to the effect of glucose deprivation. Activation of mTOR with MHY1485 prevented the effect of glucose deprivation on NNMT expression. Furthermore, upregulation of NNMT levels depended on functional autophagy and protein translation. CONCLUSION: Glucose availability regulates NNMT expression via an mTOR-dependent mechanism.


Assuntos
Adipócitos/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Glucose/farmacologia , Nicotinamida N-Metiltransferase/genética , Serina-Treonina Quinases TOR/genética , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular , Desoxiglucose/farmacologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/antagonistas & inibidores , Transportador de Glucose Tipo 4/metabolismo , Glucose-6-Fosfato Isomerase/antagonistas & inibidores , Glucose-6-Fosfato Isomerase/genética , Glucose-6-Fosfato Isomerase/metabolismo , Homeostase/genética , Camundongos , Morfolinas/farmacologia , Nicotinamida N-Metiltransferase/antagonistas & inibidores , Nicotinamida N-Metiltransferase/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Via de Pentose Fosfato/genética , Floretina/farmacologia , Biossíntese de Proteínas , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia
15.
Yi Chuan ; 42(3): 309-320, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32217516

RESUMO

Excessive accumulation of fat is harmful to human health. The preadipocyte differentiation is a critical process of fat development. Studying the expression profiles of genes related to preadipocyte differentiation contributes to understanding of the mechanism of fat accumulation. Despite being considered an ideal animal model for studying adipogenesis, little is known about the gene expression profiles at different stages during preadipocyte differentiation in rabbits. In the present study, rabbit preadipocytes were cultured in vitro and induced for differentiation, and gene expression profiles of adipocytes collected at days 0, 3, and 9 of differentiation were analyzed by RNA-seq. We identified 1352 differentially expressed genes (DEGs) when comparing day 3 with day 0 and identified 888 DEGs when comparing day 9 with day 3. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the PPAR signaling pathway and PI3K-Akt signaling pathway were significantly enriched by the DEGs that up-regulated within the period of day 0 - day 3, and the GO terms and KEGG pathways that were associated with cell cycle were enriched by the DEGs that up-regulated within the period of day 3 - day 9. The DEGs that specifically up-regulated within the period of day 0 - day 3 might play roles in the cytoplasm, and the DEGs that specifically up-regulated within the period of day 3 - day 9 might act in the nucleus. The protein-protein interaction (PPI) network constructed by DEGs showed that hub node genes might modulate rabbit preadipocyte differentiation via regulating cell cycle.


Assuntos
Adipócitos/citologia , Adipogenia , Diferenciação Celular , Transcriptoma , Animais , Perfilação da Expressão Gênica , Coelhos , Transdução de Sinais
16.
Clin Sci (Lond) ; 134(6): 629-639, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32219346

RESUMO

Adipocytes and adipose tissue are not inert and make substantial contributions to systemic metabolism by influencing energy homeostasis, insulin sensitivity, and lipid storage. In addition to well-studied hormones such as insulin, there are numerous hormones, cytokines, and growth factors that modulate adipose tissue function. Many endocrine mediators utilize the JAK-STAT pathway to mediate dozens of biological processes, including inflammation and immune responses. JAKs and STATs can modulate both adipocyte development and mature adipocyte function. Of the seven STAT family members, four STATs are expressed in adipocytes and regulated during adipogenesis (STATs 1, 3, 5A, and 5B). These STATs have been shown to play influential roles in adipose tissue development and function. STAT6, in contrast, is highly expressed in both preadipocytes and mature adipocytes, but is not considered to play a major role in regulating adipose tissue function. This review will summarize the latest research that pertains to the functions of STATs in adipocytes and adipose tissue.


Assuntos
Adipócitos/metabolismo , Fatores de Transcrição STAT/metabolismo , Adipócitos/citologia , Adipogenia , Animais , Humanos , Fatores de Transcrição STAT/genética , Transdução de Sinais
17.
Enzyme Microb Technol ; 135: 109496, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146939

RESUMO

Catechins in green tea possess various health benefits. Enzymatic treatment improves physiological activities by inducing bioconversion of catechins. Here, we investigated the effect of green tea infusion (GT) after tannase treatment, which transforms (-)-epigallocatechin gallate (EGCG) to gallic acid (GA) and (-)-epigallocatechin (EGC), on adipocyte differentiation and mature adipocyte metabolism. The optimal conditions for tannase-mediated improvement in GA and EGC yields in GT were investigated using response surface methodology. Yields of GA and EGC were 43-fold (0.43 mg/mL) and 1.66-fold higher (1.11 mg/mL), respectively, compared to GT without tannase treatment. The optimal reaction conditions for tannase-mediated biotransformation were observed on 0.54 mg mL-1 of tannase, reaction time (86.79 min), and reaction temperature at 22.59 °C. GT and tannase-treated GT (TANs) upregulated adiponectin, uncoupling protein 1, adipose triglyceride lipase, and hormone-sensitive lipase gene expression in differentiated 3T3-L1 adipocytes, with TAN inducing better effects than GT, which implies that tannase treatment improved the beneficial effect of GT on adipocyte metabolism. Thus, tannase-mediated bio-transformation is an attractive candidate for preparing GT with enhanced anti-obesity properties.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Hidrolases de Éster Carboxílico/química , Catequina/análogos & derivados , Proteínas Fúngicas/química , Extratos Vegetais/química , Adipócitos/citologia , Adiponectina/genética , Adiponectina/metabolismo , Animais , Aspergillus/enzimologia , Biocatálise , Camellia sinensis/química , Catequina/química , Catequina/farmacologia , Diferenciação Celular , Manipulação de Alimentos , Ácido Gálico/química , Ácido Gálico/farmacologia , Camundongos , Células NIH 3T3 , Extratos Vegetais/farmacologia , Folhas de Planta/química , Chá/química , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
18.
Mol Cell Biol ; 40(7)2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-31932484

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor essential for adipocyte development and the maintenance of the alternatively polarized macrophage phenotype. Biochemical studies have established that as an obligate heterodimer with retinoid X receptor (RXR), PPARγ binds directly repeated nuclear receptor half sites spaced by one nucleotide (direct repeat 1 [DR1]). However, it has not been analyzed systematically and genome-wide how cis factors such as the sequences of DR1s and adjacent sequences and trans factors such as cobinding lineage-determining transcription factors (LDTFs) contribute to the direct binding of PPARγ in different cellular contexts. We developed a novel motif optimization approach using sequence composition and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) densities from macrophages and adipocytes to complement de novo motif enrichment analysis and to define and classify high-affinity binding sites. We found that approximately half of the PPARγ cistrome represents direct DNA binding; both half sites can be extended upstream, and these are typically not of equal strength within a DR1. Strategically positioned LDTFs have greater impact on PPARγ binding than the quality of DR1, and the presence of the extension of DR1 provides a remarkable synergy with LDTFs. This approach of considering not only nucleotide frequencies but also their contribution to protein binding in a cellular context is applicable to other transcription factors.


Assuntos
Adipócitos/citologia , Proteínas de Ligação a DNA/metabolismo , Macrófagos/citologia , PPAR gama/metabolismo , Receptores X Retinoide/metabolismo , Animais , Células Cultivadas , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , Fosfoproteínas/genética , Sequências Repetitivas de Ácido Nucleico/genética , Fatores de Transcrição/genética
19.
Sci Adv ; 6(2): eaax9605, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31934629

RESUMO

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in CTNNB1/ß-catenin associated with increased obesity risk. Specific ablation of ß-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα+ preadipocytes and less mature adipocytes. Mechanistically, ß-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ß-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that ß-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ß-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/ß-catenin pathway to combat obesity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Adiposidade , Diferenciação Celular , beta Catenina/genética , Células 3T3-L1 , Tecido Adiposo Branco/metabolismo , Animais , Sítios de Ligação , Proliferação de Células , Dieta Hiperlipídica , Mutação com Ganho de Função/genética , Homeostase , Humanos , Ativação de Macrófagos , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Tamanho do Órgão , Células RAW 264.7 , Proteína Amiloide A Sérica/metabolismo , Fatores de Transcrição TCF/metabolismo , Transcrição Genética , Via de Sinalização Wnt
20.
Arch Biochem Biophys ; 681: 108260, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926163

RESUMO

Preadipocyte differentiation and lipid synthesis are critical steps for intramuscular fat (IMF) deposition and lipid metabolism homeostasis. IMF content of beef not only determines the ratio of muscle to adipose, but also determines the beef quality, flavor, and sensory characteristics. Maintaining lipid metabolism homeostasis is the key means of preventing and treating diabetes, obesity, and other metabolic diseases. SIRT6, which is an ADP-ribosyltransferase and NAD+-dependent deacetylase of acetyl and long-chain fatty acyl groups, playing central roles in lipid and glucose metabolism, is closely related to the occurrence of diabetes and obesity caused by overnutrition and aging. This study was based on bovine preadipocyte differentiation and an obese mice model, and comprehensively used transcriptome sequencing (RNA-seq) and morphological identification methods to explore the effects of inhibition of SIRT6 on differentiation and lipid synthesis, and related molecular mechanisms. Additionally, the feedback synergistic regulation of SIRT5 and SIRT6 on differentiation and lipid deposition was analyzed. The results showed that in the differentiation process of bovine preadipocytes, inhibition of SIRT5 significantly promoted SIRT6 expression. In addition, SIRT6 inhibited bovine preadipocyte differentiation and lipid synthesis, cooperating with SIRT5 to decrease lipid deposition, and repressed cell cycle arrest of preadipocytes. Moreover, in vivo verification experiments also obtained consistent results. Furthermore, SIRT6 inhibited preadipocyte differentiation and lipid deposition by activating the adenosine monophosphate activated protein kinase alpha (AMPKα) pathway. The above results provided a novel approach for understanding the functions of SIRT6 in regulating bovine adipocyte differentiation and lipid metabolism, as well as a new target for the treatment of diabetes and obesity in a clinical setting.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia , Metabolismo dos Lipídeos , Transdução de Sinais , Sirtuínas/metabolismo , Adipócitos/citologia , Animais , Bovinos , Diferenciação Celular , Células Cultivadas
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