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1.
Cells ; 10(12)2021 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-34943840

RESUMO

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide-gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp-/- mice. Neutrophil infiltration was lessened in the liver of Camp-/- mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp-/- mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp-/- mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp-/- mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.


Assuntos
Adiponectina/metabolismo , Catelicidinas/deficiência , Dieta Hiperlipídica/efeitos adversos , Etanol/efeitos adversos , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/lesões , Fígado/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Animais , Catelicidinas/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/complicações , Comportamento Alimentar , Hipertrofia , Inflamação/patologia , Lipólise , Fígado/patologia , Masculino , Camundongos , Ganho de Peso
2.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639094

RESUMO

Insulin stimulates glucose uptake in adipose tissue and skeletal muscle by inducing plasma membrane translocation of the glucose transporter GLUT4. Although the small GTPase Rac1 is a key regulator downstream of phosphoinositide 3-kinase (PI3K) and the protein kinase Akt2 in skeletal muscle, it remains unclear whether Rac1 also regulates glucose uptake in white adipocytes. Herein, we investigated the physiological role of Rac1 in white adipocytes by employing adipocyte-specific rac1 knockout (adipo-rac1-KO) mice. Subcutaneous and epididymal white adipose tissues (WATs) in adipo-rac1-KO mice showed significant reductions in size and weight. Actually, white adipocytes lacking Rac1 were smaller than controls. Insulin-stimulated glucose uptake and GLUT4 translocation were abrogated in rac1-KO white adipocytes. On the other hand, GLUT4 translocation was augmented by constitutively activated PI3K or Akt2 in control, but not in rac1-KO, white adipocytes. Similarly, to skeletal muscle, the involvement of another small GTPase RalA downstream of Rac1 was demonstrated. In addition, mRNA levels of various lipogenic enzymes were down-regulated in rac1-KO white adipocytes. Collectively, these results suggest that Rac1 is implicated in insulin-dependent glucose uptake and lipogenesis in white adipocytes, and reduced insulin responsiveness due to the deficiency of Rac1 may be a likely explanation for atrophy of WATs.


Assuntos
Tecido Adiposo Branco/patologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Insulina/farmacologia , Neuropeptídeos/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Atrofia , Feminino , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edulcorantes/farmacologia
3.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502347

RESUMO

Brown adipose tissue (BAT), a uniquely thermogenic tissue that plays an important role in metabolism and energy expenditure, has recently become a revived target in the fight against metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). Different from white adipose tissue (WAT), the brown adipocytes have distinctive features including multilocular lipid droplets, a large number of mitochondria, and a high expression of uncoupling protein-1 (UCP-1), as well as abundant capillarity. These histologic characteristics provide an opportunity to differentiate BAT from WAT using imaging modalities, such as PET/CT, SPECT/CT, MRI, NIRF and Ultrasound. However, most of the reported imaging methods were BAT activation dependent, and the imaging signals could be affected by many factors, including environmental temperatures and the states of the sympathetic nervous system. Accurate BAT mass detection methods that are independent of temperature and hormone levels have the capacity to track the development and changes of BAT throughout the lifetime of mammals, and such methods could be very useful for the investigation of potential BAT-related therapies. In this review, we focus on molecular imaging modalities that can detect and quantify BAT mass. In addition, their detection mechanism and limitations will be discussed as well.


Assuntos
Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Doenças Metabólicas/diagnóstico , Imagem Molecular/métodos , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Branco/diagnóstico por imagem , Animais , Humanos
4.
Biochem Pharmacol ; 192: 114723, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364887

RESUMO

Both obesity and aging are associated with the development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation of adipose tissue is one of the mechanisms implicated in the progression of these diseases. Obesity and aging trigger adipose tissue alterations that ultimately lead to a pro-inflammatory phenotype of the adipose tissue-resident immune cells. Obesity and aging also share other features such as a higher visceral vs. subcutaneous adipose tissue ratio and a decreased lifespan. Here, we review the common characteristics of obesity and aging and the alterations in white adipose tissue and resident immune cells. We focus on the adipose tissue metabolic derangements in obesity and aging such as inflammation and adipose tissue remodeling.


Assuntos
Adipócitos Brancos/imunologia , Tecido Adiposo Branco/imunologia , Envelhecimento/imunologia , Distribuição da Gordura Corporal/métodos , Obesidade/imunologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Humanos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Obesidade/metabolismo , Obesidade/patologia
5.
Cells ; 10(8)2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34440723

RESUMO

Mice lacking the functional cystinosin gene (Ctns-/-), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns-/- mice. We treated 12-month-old Ctns-/- mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns-/- mice. PLA attenuated adipose tissue browning in Ctns-/- mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns-/- mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns-/- mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns-/- mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Caquexia/prevenção & controle , Cistinose/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Receptores para Leptina/antagonistas & inibidores , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/patologia , Cistinose/complicações , Cistinose/metabolismo , Cistinose/patologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Receptores para Leptina/metabolismo , Transdução de Sinais
6.
Sci Rep ; 11(1): 13923, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230537

RESUMO

Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.


Assuntos
Tecido Adiposo Branco/patologia , Dieta , Obesidade/patologia , Células-Tronco/patologia , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Biomarcadores/metabolismo , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Inflamação/genética , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Feocromocitoma/patologia , Ganho de Peso
7.
Cell Death Dis ; 12(7): 666, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215724

RESUMO

High-mobility group box 2 (HMGB2) is an abundant, chromatin-associated protein that plays an essential role in the regulation of transcription, cell proliferation, differentiation, and tumorigenesis. However, the underlying mechanism of HMGB2 in adipogenesis remains poorly known. Here, we provide evidence that HMGB2 deficiency in preadipocytes impedes adipogenesis, while overexpression of HMGB2 increases the potential for adipogenic differentiation. Besides, depletion of HMGB2 in vivo caused the decrease in body weight, white adipose tissue (WAT) mass, and adipocyte size. Consistently, the stromal vascular fraction (SVF) of adipose tissue derived from hmgb2-/- mice presented impaired adipogenesis. When hmgb2-/- mice were fed with high-fat diet (HFD), the body size, and WAT mass were increased, but at a lower rate. Mechanistically, HMGB2 mediates adipogenesis via enhancing expression of C/EBPß by binding to its promoter at "GGGTCTCAC" specifically during mitotic clonal expansion (MCE) stage, and exogenous expression of C/EBPß can rescue adipogenic abilities of preadipocytes in response to HMGB2 inhibition. In general, our findings provide a novel mechanism of HMGB2-C/EBPß axis in adipogenesis and a potential therapeutic target for obesity.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína HMGB2/metabolismo , Mitose , Obesidade/metabolismo , Regiões Promotoras Genéticas , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Animais , Sítios de Ligação , Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Proteína HMGB2/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Transdução de Sinais , Ganho de Peso
8.
FASEB J ; 35(8): e21760, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34309918

RESUMO

White adipose tissue (WAT) has the capacity to undergo a white-to-beige phenotypic switch, known as browning, in response to stimuli such as cold. However, the mechanism underlying beige adipocyte formation is largely unknown. Apolipoprotein E (ApoE) is highly induced in WAT and has been implicated in lipid metabolism. Here, we show that ApoE deficiency in mice increased oxygen consumption and thermogenesis and enhanced adipose browning pattern in inguinal WAT (iWAT), with associated characteristics such as increased Ucp1 and Pparγ expression. At the cellular level, ApoE deficient beige adipocytes had increased glucose uptake and higher mitochondrial respiration than wild-type cells. Mechanistically, we showed that ApoE deficient iWAT and primary adipose precursor cells activated the thermogenic genes program by stimulating the production of ketone body ß-hydroxybutyrate (ßHB), a novel adipose browning promoting factor. This was accompanied by increased expression of genes involved in ketogenesis and could be compromised by the treatment for ketogenesis inhibitors. Consistently, ApoE deficient mice show higher serum ßHB level than wild-type mice in the fed state and during cold exposure. Our results further demonstrate that the increased ßHB production in ApoE deficient adipose precursor cells could be attributed, at least in part, to enhanced Cd36 expression and CD36-mediated fatty acid utilization. Our findings uncover a previously uncharacterized role for ApoE in energy homeostasis via its cell-autonomous action in WAT.


Assuntos
Ácido 3-Hidroxibutírico/biossíntese , Tecido Adiposo Branco , Apolipoproteínas E/deficiência , Metabolismo Energético , Termogênese , Adipócitos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Células Cultivadas , Fibroblastos , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
9.
Front Immunol ; 12: 664576, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093556

RESUMO

Type 2 diabetes (T2D) is a rising global health problem mainly caused by obesity and a sedentary lifestyle. In healthy individuals, white adipose tissue (WAT) has a relevant homeostatic role in glucose metabolism, energy storage, and endocrine signaling. Mast cells contribute to these functions promoting WAT angiogenesis and adipogenesis. In patients with T2D, inflammation dramatically impacts WAT functioning, which results in the recruitment of several leukocytes, including monocytes, that enhance this inflammation. Accordingly, the macrophages population rises as the WAT inflammation increases during the T2D status worsening. Since mast cell progenitors cannot arrive at WAT, the amount of WAT mast cells depends on how the new microenvironment affects progenitor and differentiated mast cells. Here, we employed a flow cytometry-based approach to analyze the number of mast cells from omental white adipose tissue (o-WAT) and subcutaneous white adipose tissue (s-WAT) in a cohort of 100 patients with obesity. Additionally, we measured the number of mast cell progenitors in a subcohort of 15 patients. The cohort was divided in three groups: non-T2D, pre-T2D, and T2D. Importantly, patients with T2D have a mild condition (HbA1c <7%). The number of mast cells and mast cell progenitors was lower in patients with T2D in both o-WAT and s-WAT in comparison to subjects from the pre-T2D and non-T2D groups. In the case of mast cells in o-WAT, there were statistically significant differences between non-T2D and T2D groups (p = 0.0031), together with pre-T2D and T2D groups (p=0.0097). However, in s-WAT, the differences are only between non-T2D and T2D groups (p=0.047). These differences have been obtained with patients with a mild T2D condition. Therefore, little changes in T2D status have a huge impact on the number of mast cells in WAT, especially in o-WAT. Due to the importance of mast cells in WAT physiology, their decrease can reduce the capacity of WAT, especially o-WAT, to store lipids and cause hypoxic cell deaths that will trigger inflammation.


Assuntos
Tecido Adiposo/patologia , Contagem de Células , Diabetes Mellitus Tipo 2/patologia , Mastócitos/patologia , Obesidade/patologia , Adipogenia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Biomarcadores , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Imunofenotipagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Neovascularização Fisiológica , Obesidade/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 321(1): H228-H241, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34018851

RESUMO

Adipose tissue homeostasis plays a central role in cardiovascular physiology, and the presence of thermogenically active brown adipose tissue (BAT) has recently been associated with cardiometabolic health. We have previously shown that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) reduces BAT-mediated adaptive thermogenesis, and the goal of this work was to identify the cardiovascular impacts of Adipo-HuR-/-. We found that Adipo-HuR-/- mice exhibit a hypercontractile phenotype that is accompanied by increased left ventricle wall thickness and hypertrophic gene expression. Furthermore, hearts from Adipo-HuR-/- mice display increased fibrosis via picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene coexpression network analysis (WGCNA) across both cardiac and adipose tissue to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and cardiac fibrosis. RNA-seq results demonstrated a significant increase in proinflammatory gene expression in both cardiac and subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. In addition to inflammation-related genes, WGCNA identified a significant enrichment in extracellular vesicle-mediated transport and exosome-associated genes in scWAT, whose expression most significantly associated with the degree of cardiac fibrosis observed in Adipo-HuR-/- mice, implicating these processes as a likely adipose-to-cardiac paracrine mechanism. These results are significant in that they demonstrate the spontaneous onset of cardiovascular pathology in an adipose tissue-specific gene deletion model and contribute to our understanding of how disruptions in adipose tissue homeostasis may mediate cardiovascular disease.NEW & NOTEWORTHY The presence of functional brown adipose tissue in humans is known to be associated with cardiovascular health. Here, we show that adipocyte-specific deletion of the RNA binding protein HuR, which we have previously shown to reduce BAT-mediated thermogenesis, is sufficient to mediate a spontaneous development of cardiac hypertrophy and fibrosis. These results may have implications on the mechanisms by which BAT function and adipose tissue homeostasis directly mediate cardiovascular disease.


Assuntos
Adipócitos/metabolismo , Cardiomegalia/genética , Proteína Semelhante a ELAV 1/genética , Miocárdio/metabolismo , Adipócitos/patologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteína Semelhante a ELAV 1/metabolismo , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Camundongos , Camundongos Knockout , Miocárdio/patologia
11.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34003802

RESUMO

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.


Assuntos
Tecido Adiposo Branco/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Resistência à Insulina , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Aminoácidos de Cadeia Ramificada/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/patologia
12.
Int J Biol Macromol ; 182: 1371-1383, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34004199

RESUMO

Microalgae are emerging as a good source of natural nutraceuticals and medicines. This study aims at evaluating the anti-obesity effects of two microalgae polysaccharides (CPS from Chlorella pyrenoidosa and SPS from Spirulina platensis) in high-fat diet (HFD)-induced obese C57BL/6 mice, with ß-glucan as a positive control polysaccharide. CPS, SPS and ß-glucan were daily administered intragastrically during 10-week HFD feeding, and conferred equally effective protection against overweight, energy imbalance, glucose tolerance impairment, systemic inflammation, dyslipidemia, and fat deposition in the liver and epididymal white adipose tissues. By western blotting analysis of CPT-1, PPARγ and SREBP-1c, those polysaccharides increased lipolysis and decreased lipogenesis in the liver. According to high-throughput sequencing of fecal 16S rRNA, CPS, SPS and ß-glucan corrected the HFD-induced gut dysbiosis similarly by increasing beneficial bacteria especially Clostridia, Bacterioidia and Mollicutes and decreasing unfavorable bacteria especially Actinobacteria and Verrucomicrobia and, as revealed by PICRUSt functional analysis, they restored the HFD-induced perturbations in many gut bacterial enzymes and pathways involved in the metabolism of SCFAs, secondary bile acids and trimethylamine, implicating a possible anti-obesity mechanism through gut microbiome-mediated modulation of host lipid metabolism. Microalgae polysaccharides can thus serve as potent alternative food ingredients to improve disease conditions in obese patients.


Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Microalgas/química , Obesidade/tratamento farmacológico , Obesidade/microbiologia , Polissacarídeos/uso terapêutico , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Administração Oral , Animais , Bactérias/classificação , Bactérias/genética , Dislipidemias/complicações , Metabolismo Energético/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Monossacarídeos/análise , Obesidade/metabolismo , Filogenia , Polissacarídeos/administração & dosagem , Polissacarídeos/farmacologia
13.
Endocrinology ; 162(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33963396

RESUMO

CONTEXT: Healthy hyperplasic (many but smaller fat cells) white adipose tissue (WAT) expansion is mediated by recruitment, proliferation and/or differentiation of new fat cells. This process (adipogenesis) is controlled by transcriptional programs that have been mostly identified in rodents. OBJECTIVE: A systemic investigation of adipogenic human transcription factors (TFs) that are relevant for metabolic conditions has not been revealed previously. METHODS: TFs regulated in WAT by obesity, adipose morphology, cancer cachexia, and insulin resistance were selected from microarrays. Their role in differentiation of human adipose tissue-derived stem cells (hASC) was investigated by RNA interference (RNAi) screen. Lipid accumulation, cell number, and lipolysis were measured for all screened factors (148 TFs). RNA (RNAseq), protein (Western blot) expression, insulin, and catecholamine responsiveness were examined in hASC following siRNA treatment of selected target TFs. RESULTS: Analysis of TFs regulated by metabolic conditions in human WAT revealed that many of them belong to adipogenesis-regulating pathways. The RNAi screen identified 39 genes that affected fat cell differentiation in vitro, where 11 genes were novel. Of the latter JARID2 stood out as being necessary for formation of healthy fat cell metabolic phenotype by regulating expression of multiple fat cell phenotype-specific genes. CONCLUSION: This comprehensive RNAi screening in hASC suggests that a large proportion of WAT TFs that are impacted by metabolic conditions might be important for hyperplastic adipose tissue expansion. The screen also identified JARID2 as a novel TF essential for the development of functional adipocytes.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Complexo Repressor Polycomb 2/genética , Interferência de RNA/fisiologia , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Adipócitos/química , Adipócitos/patologia , Tecido Adiposo Branco/química , Tecido Adiposo Branco/patologia , Adolescente , Sequência de Bases , Diferenciação Celular/genética , Células Cultivadas , Feminino , Neoplasias Gastrointestinais , Regulação da Expressão Gênica , Humanos , Hiperplasia/genética , Resistência à Insulina/genética , Masculino , Obesidade/genética , Complexo Repressor Polycomb 2/fisiologia , Células-Tronco/química , Fatores de Transcrição/fisiologia
14.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803198

RESUMO

Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.


Assuntos
Tecido Adiposo Branco/metabolismo , Matriz Extracelular/metabolismo , Doenças Metabólicas/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Animais , Matriz Extracelular/genética , Matriz Extracelular/patologia , Estudo de Associação Genômica Ampla , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Músculo Esquelético/patologia , Obesidade/genética , Obesidade/patologia
15.
Am J Physiol Endocrinol Metab ; 320(6): E1148-E1157, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33870712

RESUMO

The cytokine interleukin 4 (IL-4) can increase beige adipogenesis in adult rodents. However, neonatal animals use a distinct adipocyte precursor compartment for adipogenesis as compared with adults. In this study, we address whether IL-4 can induce persistent effects on adipose tissue when administered subcutaneously in the interscapular region during the neonatal period in Sprague-Dawley rats. We injected IL-4 into neonatal male rats during postnatal days 1-6, followed by analysis of adipose tissue and adipocyte precursors at 2 wk and 10 wk of age. Adipocyte precursors were cultured and subjected to differentiation in vitro. We found that a short and transient IL-4 exposure in neonates upregulated uncoupling protein 1 (Ucp1) mRNA expression and decreased fat cell size in subcutaneous white adipose tissue (WAT). Adipocyte precursors from mature rats that had been treated with IL-4 as neonates displayed a decrease in adiponectin (Adipoq) but no change in Ucp1 expression, as compared with controls. Thus, neonatal IL-4 induces acute beige adipogenesis and decreases adipogenic differentiation capacity long term. Overall, these findings indicate that the neonatal period is critical for adipocyte development and may influence the later onset of obesity.NEW & NOTEWORTHY We used neonatal injections in rat to show that IL-4 decreases adipogenesis and increases browning of white fat. In adulthood, adipocyte precursors show persistently decreased adipogenesis but not increased browning. These studies in the neonate are the first, to our knowledge, to show that IL-4 can have long-lasting effects.


Assuntos
Adipogenia/efeitos dos fármacos , Envelhecimento/metabolismo , Interleucina-4/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Envelhecimento/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
16.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670146

RESUMO

White adipose tissue (WAT) is involved in long-term energy storage and represents 10-15% of total body weight in healthy humans. WAT secretes many peptides (adipokines), hormones and steroids involved in its homeostatic role, especially in carbohydrate-lipid metabolism regulation. Recently, adipocyte-derived extracellular vesicles (AdEVs) have been highlighted as important actors of intercellular communication that participate in metabolic responses to control energy flux and immune response. In this review, we focus on the role of AdEVs in the cross-talks between the different cellular types composing WAT with regard to their contribution to WAT homeostasis and metabolic complications development. We also discuss the AdEV cargoes (proteins, lipids, RNAs) which may explain AdEV's biological effects and demonstrate that, in terms of proteins, AdEV has a very specific signature. Finally, we list and suggest potential therapeutic strategies to modulate AdEV release and composition in order to reduce their deleterious effects during the development of metabolic complications associated with obesity.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Comunicação Celular , Vesículas Extracelulares/metabolismo , Obesidade/metabolismo , Obesidade/terapia , Adipócitos/patologia , Adipocinas/metabolismo , Tecido Adiposo Branco/patologia , Animais , Vesículas Extracelulares/patologia , Humanos , Obesidade/patologia
17.
Molecules ; 26(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671428

RESUMO

The potential biological activities of Viburnum stellato-tomentosum (VS), a plant mainly found in Costa Rica, have yet to be reported. Supplementation of VS extract for 17 weeks significantly decreased body weight gain, fat weight, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride levels in high-fat diet (HFD)-fed C57BL/6J mice. The molecular mechanisms underlying the anti-obesity and glucose-lowering effects of VS extract were investigated. VS extract suppressed adipocyte hypertrophy by regulating lipogenesis-related CCAAT/enhancer-binding protein α (C/EBPα) and insulin sensitivity-related peroxisome proliferator-activated receptor γ (Pparg) expression in adipose tissue (AT) and hepatic steatosis by inhibiting C/EBPα and lipid transport-related fatty acid binding protein 4 (FABP4) expression. VS extract enhanced muscular fatty acid ß-oxidation-related AMP-activated protein kinase (AMPK) and PPARα expression with increasing Pparg levels. Furthermore, VS extract contained a much higher content of amentoflavone (AMF) (29.4 mg/g extract) compared to that in other Viburnum species. AMF administration decreased Cebpa and Fabp4 levels in the AT and liver, as well as improved insulin signaling-related insulin receptor substrate 1 (Irs1) and glucose transporter 1 (Glut1) levels in the muscle of HFD-fed mice. This study elucidated the in vivo molecular mechanisms of AMF for the first time. Therefore, VS extract effectively diminished obesity and hyperglycemia by suppressing C/EBPα-mediated lipogenesis in the AT and liver, enhancing PPARα-mediated fatty acid ß-oxidation in muscle, and PPARγ-mediated insulin sensitivity in AT and muscle.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Hiperglicemia/tratamento farmacológico , Metabolismo dos Lipídeos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/uso terapêutico , Viburnum/química , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Fármacos Antiobesidade/farmacologia , Biflavonoides/farmacologia , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/tratamento farmacológico , Comportamento Alimentar , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipertrofia , Insulina/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/complicações , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos
18.
Cells ; 10(2)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669222

RESUMO

Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as "browning" or "beiging". These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.


Assuntos
Adipogenia , Tecido Adiposo Branco/patologia , Reação de Maillard , Células-Tronco Mesenquimais/citologia , Obesidade/patologia , Adipogenia/genética , Apoptose , Biomarcadores/metabolismo , Proliferação de Células , Senescência Celular , Regulação da Expressão Gênica , Humanos , Gotículas Lipídicas/metabolismo , Mitocôndrias/metabolismo , Consumo de Oxigênio , Proteína Desacopladora 1/metabolismo
19.
J Vis Exp ; (167)2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33522508

RESUMO

Cancer cachexia (CC) presents itself as a syndrome with multiple manifestations, causing a marked multi-organ metabolic imbalance. Recently, cachectic wasting has been proposed to be stimulated by several inflammatory mediators, which may disrupt the integrative physiology of adipose tissues and other tissues such as the brain and muscle. In this scenario, the tumor can survive at the host's expense. In recent clinical research, the intensity of depletion of the different fat deposits has been negatively correlated with the patient's survival outcome. Studies have also shown that various metabolic disorders can alter white adipose tissue (WAT) remodeling, especially in the early stages of cachexia development. WAT dysfunction resulting from tissue remodeling is a contributor to overall cachexia, with the main modifications in WAT consisting of morpho-functional changes, increased adipocyte lipolysis, accumulation of immune cells, reduction of adipogenesis, changes in progenitor cell population, and the increase of "niches" containing beige/brite cells. To study the various facets of cachexia-induced WAT remodeling, particularly the changes progenitor cells and beige remodeling, two-dimensional (2D) culture has been the first option for in vitro studies. However, this approach does not adequately summarize WAT complexity. Improved assays for the reconstruction of functional AT ex vivo help the comprehension of physiological interactions between the distinct cell populations. This protocol describes an efficient three-dimensional (3D) printing tissue culture system based on magnetic nanoparticles. The protocol is optimized for investigating WAT remodeling induced by cachexia induced factors (CIFs). The results show that a 3D culture is an appropriate tool for studying WAT modeling ex vivo and may be useful for functional screens to identify bioactive molecules for individual adipose cell populations applications and aid the discovery of WAT-based cell anticachectic therapy.


Assuntos
Adipócitos/patologia , Tecido Adiposo Branco/patologia , Caquexia/patologia , Técnicas de Cultura de Células/métodos , Modelos Biológicos , Adipócitos/metabolismo , Animais , Carcinoma Pulmonar de Lewis/patologia , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Perilipina-1/metabolismo , Esferoides Celulares/patologia , Células Estromais/patologia , Proteína Desacopladora 1/metabolismo
20.
Eur J Endocrinol ; 184(4): 533-541, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524007

RESUMO

Context: The endocrine and immunological properties of subcutaneous vs visceral adipose tissue (sWAT and vWAT, respectively) have turned a milestone in the study of metabolic diseases. The cytokine S100A4 is increased in obesity and has a role in adipose tissue dysfunction. However, the cellular source and its potential role in hepatic damage in obesity has not been elucidated. Objective: We aim to study the regulation of S100A4 in immune cells present in sWAT and vWAT, as well as its potential role as a circulating marker of hepatic inflammation and steatosis. Design: A cohort of 60 patients with obesity and distinct metabolic status was analyzed. CD11b+ myeloid cells and T cells were isolated from sWAT and vWAT by magnetic-activating cell sorting, and RNA was obtained. S100A4 gene expression was measured, and correlation analysis with clinical data was performed. Liver biopsies were obtained from 20 patients, and S100A4 circulating levels were measured to check the link with hepatic inflammation and steatosis. Results: S100A4 gene expression was strongly upregulated in sWAT- vs vWAT-infiltrated CD11b+ cells, but this modulation was not observed in T cells. S100A4 mRNA levels from sWAT (and not from vWAT) CD11b+ cells positively correlated with glycemia, triglycerides, TNF-α gene expression and proliferation markers. Finally, circulating S100A4 directly correlated with liver steatosis and hepatic inflammatory markers. Conclusion: Our data suggest that sWAT-infiltrated CD11b+ cells could be a major source of S100A4 in obesity. Moreover, our correlations identify circulating S100A4 as a potential novel biomarker of hepatic damage and steatosis.


Assuntos
Tecido Adiposo Branco/patologia , Antígeno CD11b/análise , Fígado Gorduroso/sangue , Células Mieloides/química , Obesidade/complicações , Proteína A4 de Ligação a Cálcio da Família S100/análise , Tecido Adiposo Branco/química , Tecido Adiposo Branco/metabolismo , Adulto , Idoso , Animais , Biomarcadores/análise , Biomarcadores/sangue , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Humanos , Gordura Intra-Abdominal/química , Gordura Intra-Abdominal/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Células RAW 264.7 , Proteína A4 de Ligação a Cálcio da Família S100/sangue , Proteína A4 de Ligação a Cálcio da Família S100/genética , Gordura Subcutânea/química , Gordura Subcutânea/patologia
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