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1.
J Vis Exp ; (162)2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32894273

RESUMO

Obesity is a major worldwide public health issue that increases the risk to develop cardiovascular diseases, type-2 diabetes, and liver diseases. Obesity is characterized by an increase in adipose tissue (AT) mass due to adipocyte hyperplasia and/or hypertrophia, leading to profound remodeling of its three-dimensional structure. Indeed, the maximal capacity of AT to expand during obesity is pivotal to the development of obesity-associated pathologies. This AT expansion is an important homeostatic mechanism to enable adaptation to an excess of energy intake and to avoid deleterious lipid spillover to other metabolic organs, such as muscle and liver. Therefore, understanding the structural remodeling that leads to the failure of AT expansion is a fundamental question with high clinical applicability. In this article, we describe a simple and fast clearing method that is routinely used in our laboratory to explore the morphology of mouse and human white adipose tissue by fluorescent imaging. This optimized AT clearing method is easily performed in any standard laboratory equipped with a chemical hood, a temperature-controlled orbital shaker and a fluorescent microscope. Moreover, the chemical compounds used are readily available. Importantly, this method allows one to resolve the 3D AT structure by staining various markers to specifically visualize the adipocytes, the neuronal and vascular networks, and the innate and adaptive immune cells distribution.


Assuntos
Tecido Adiposo/patologia , Imageamento Tridimensional , Salicilatos/farmacocinética , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Humanos , Camundongos , Microscopia de Fluorescência , Obesidade/metabolismo , Obesidade/patologia
2.
Toxicol Lett ; 334: 27-35, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956827

RESUMO

Methyl- and propyl- parabens are generally regarded as safe by the U.S Food and Drug Administration and as such are commonly used in personal care products. These parabens have been associated with increased white adipogenesis in vitro and methyl paraben also increased the white adipose mass of mice. Given brown adipose also plays a role in energy balance, we sought to evaluate whether the effects of methyl- and propyl- parabens on white adipocytes extended to brown adipocytes. We challenged white and brown pre-adipocytes at low doses of both parabens (up to 1 µM) during the differentiation process and examined adipogenesis with the ORO assay. The impact of each paraben on glucose uptake and lipolytic activity of adipocytes were measured with a fluorescent glucose analog and enzymatically, respectively. Methyl- and propyl- parabens increased adipogenesis of 3T3-L1 white adipocytes but not brown adipocytes. In white adipocytes, methyl paraben increased glucose uptake and both parabens reduced basal lipolysis. However, in brown adipocytes, parabens had no effect on basal lipolysis and instead attenuated isoproterenol induced lipolysis. These data indicate that methyl- and propyl- parabens target the differentiation and metabolic processes of multiple types of adipocytes in a cell autonomous manner.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Parabenos/toxicidade , Conservantes Farmacêuticos/toxicidade , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Cosméticos , Glucose/metabolismo , Lipólise/efeitos dos fármacos , Camundongos
3.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
4.
Mol Cell ; 79(6): 934-949.e14, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32822587

RESUMO

Although ADP-ribosylation of histones by PARP-1 has been linked to genotoxic stress responses, its role in physiological processes and gene expression has remained elusive. We found that NAD+-dependent ADP-ribosylation of histone H2B-Glu35 by small nucleolar RNA (snoRNA)-activated PARP-1 inhibits AMP kinase-mediated phosphorylation of adjacent H2B-Ser36, which is required for the proadipogenic gene expression program. The activity of PARP-1 on H2B requires NMNAT-1, a nuclear NAD+ synthase, which directs PARP-1 catalytic activity to Glu and Asp residues. ADP-ribosylation of Glu35 and the subsequent reduction of H2B-Ser36 phosphorylation inhibits the differentiation of adipocyte precursors in cultured cells. Parp1 knockout in preadipocytes in a mouse lineage-tracing genetic model increases adipogenesis, leading to obesity. Collectively, our results demonstrate a functional interplay between H2B-Glu35 ADP-ribosylation and H2B-Ser36 phosphorylation that controls adipogenesis.


Assuntos
ADP-Ribosilação/genética , Adipogenia/genética , Histonas/genética , Poli(ADP-Ribose) Polimerase-1/genética , Adenosina Difosfato Ribose/genética , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Linhagem Celular , Dano ao DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Fosforilação/genética , RNA Nucleolar Pequeno/genética
5.
Anim Sci J ; 91(1): e13449, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32815204

RESUMO

Ectopic fats have been recognized as a new risk factor for metabolic syndrome. In obese humans, ectopic fat accumulations are affected by body fat distribution. Intramuscular adipose tissue is categorized as one of the ectopic fats. Japanese black cattle (Wagyu) are characterized by the ability to accumulate high amounts of intramuscular adipose tissue. In Japan, the marbling level is indicated by the beef marbling standard number (BMS No.), which reflects the intramuscular fat content of longissimus muscle. We hypothesized that the intramuscular fat accumulation is affected by the body fat distribution in Wagyu cattle. In this study, we showed that the BMS No. was not correlated with the subcutaneous and visceral adipocyte diameter. In contrast, the BMS No. was positively correlated with intramuscular adipocyte diameter. These results indicate that the intramuscular adipocyte diameter of Wagyu is hypertrophied with an increase in the intramuscular fat accumulation. In addition, we showed that the BMS No. was positively correlated with the subcutaneous fat percentage. In contrast, the BMS No. was negatively correlated with the visceral fat percentage. These results indicate that highly marbled Wagyu cattle have a higher percentage of subcutaneous fat and a lower percentage of visceral fat.


Assuntos
Adipócitos/patologia , Adipogenia , Distribuição da Gordura Corporal , Bovinos/metabolismo , Qualidade dos Alimentos , Gordura Intra-Abdominal/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Carne Vermelha/normas , Gordura Subcutânea/metabolismo , Animais , Masculino
6.
Breast Cancer Res ; 22(1): 81, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736587

RESUMO

BACKGROUND: Previous studies have identified and validated a risk-associated Active transcriptome phenotype commonly expressed in the cancer-adjacent and histologically normal epithelium, stroma, and adipose containing peritumor microenvironment of clinically established invasive breast cancers, conferring a 2.5- to 3-fold later risk of dying from recurrent breast cancer. Expression of this Active transcriptome phenotype has not yet been evaluated in normal breast tissue samples unassociated with any benign or malignant lesions; however, it has been associated with increased peritumor adipocyte composition. METHODS: Detailed histologic and transcriptomic (RNAseq) analyses were performed on normal breast biopsy samples from 151 healthy, parous, non-obese (mean BMI = 29.60 ± 7.92) women, ages 27-66 who donated core breast biopsy samples to the Komen Tissue Bank, and whose average breast cancer risk estimate (Gail score) at the time of biopsy (1.27 ± 1.34) would not qualify them for endocrine prevention therapy. RESULTS: Full genome RNA sequencing (RNAseq) identified 52% (78/151) of these normal breast samples as expressing the Active breast phenotype. While Active signature genes were found to be most variably expressed in mammary adipocytes, donors with the Active phenotype had no difference in BMI but significantly higher Gail scores (1.46 vs. 1.18; p = 0.007). Active breast samples possessed 1.6-fold more (~ 80%) adipocyte nuclei, larger cross-sectional adipocyte areas (p < 0.01), and 0.5-fold fewer stromal and epithelial cell nuclei (p < 1e-6). Infrequent low-level expression of cancer gene hotspot mutations was detected but not enriched in the Active breast samples. Active samples were enriched in gene sets associated with adipogenesis and fat metabolism (FDR q ≤ 10%), higher signature scores for cAMP-dependent lipolysis known to drive breast cancer progression, white adipose tissue browning (Wilcoxon p < 0.01), and genes associated with adipocyte activation (leptin, adiponectin) and remodeling (CAV1, BNIP3), adipokine growth factors (IGF-1, FGF2), and pro-inflammatory fat signaling (IKBKG, CCL13). CONCLUSIONS: The risk-associated Active transcriptome phenotype first identified in cancer-adjacent breast tissues also occurs commonly in healthy women without breast disease who do not qualify for breast cancer chemoprevention, and independently of breast expressed cancer-associated mutations. The risk-associated Active phenotype appears driven by a pro-tumorigenic adipocyte microenvironment that can predate breast cancer development.


Assuntos
Adipócitos/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adipócitos/metabolismo , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Fenótipo , Prognóstico , Transcriptoma
7.
Am J Physiol Endocrinol Metab ; 319(2): E363-E375, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603262

RESUMO

Bone morphogenetic protein (BMP) receptor signaling is critical for the regulation of the endocrine system and cardiovascular structure and function. The objective of this study was to investigate whether Bmp3b, a glycoprotein synthetized and secreted by adipose tissue, is necessary to regulate glucose and lipid metabolism, adipogenesis, and cardiovascular remodeling. Over the course of 4 mo, Bmp3b-knockout (Bmp3b-/-) mice gained more weight than wild-type (WT) mice. The plasma levels of cholesterol and triglycerides were higher in Bmp3b-/- mice than in WT mice. Bmp3b-/- mice developed insulin resistance and glucose intolerance. The basal heart rate was higher in Bmp3b-/- mice than in WT mice, and echocardiography revealed eccentric remodeling in Bmp3b-/- mice. The expression of adipogenesis-related genes in white adipose tissue was higher in Bmp3b-/- mice than in WT control mice. In vitro studies showed that Bmp3b modulates the activity of the C/ebpα promoter, an effect mediated by Smad2/3. The results of this study suggest that Bmp3b is necessary for the maintenance of homeostasis in terms of age-related weight gain, glucose metabolism, and left ventricular (LV) remodeling and function. Interventions that increase the level or function of BMP3b may decrease cardiovascular risk and pathological cardiac remodeling.


Assuntos
Adipogenia/fisiologia , Fator 10 de Diferenciação de Crescimento/deficiência , Fator 10 de Diferenciação de Crescimento/fisiologia , Síndrome Metabólica/etiologia , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Proteína Morfogenética Óssea 3/deficiência , Proteína Morfogenética Óssea 3/fisiologia , Dislipidemias/etiologia , Feminino , Intolerância à Glucose/etiologia , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Transdução de Sinais/fisiologia
8.
Clin Sci (Lond) ; 134(12): 1537-1553, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32556103

RESUMO

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.


Assuntos
Adipócitos/patologia , Tecido Adiposo Bege/patologia , Tecido Adiposo Branco/patologia , Ácidos Graxos não Esterificados/sangue , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Resistência à Insulina , Metformina/uso terapêutico , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Adulto , Animais , Ativação Enzimática , Feminino , Humanos , Hipertrofia , Leptina/metabolismo , Lipogênese , Lipólise , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais , Triglicerídeos/metabolismo , Ácido Úrico/sangue
9.
Am J Physiol Endocrinol Metab ; 319(2): E254-E264, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484712

RESUMO

Adipose tissue inflammation, as defined by macrophage accumulation, is proposed to cause insulin resistance and systemic inflammation. Because the strength of this relationship for humans is unclear, we tested whether adipose tissue macrophage (ATM) burden is correlated with these health indicators. Using immunohistochemistry, we measured abdominal subcutaneous CD68+ (total ATM), CD14+ (proinflammatory/M1), and CD206+ (anti-inflammatory/M2) ATM in 97 volunteers (BMI 20-38 kg/m2, in addition to body composition, adipocyte size, homeostasis model assessment of insulin resistance, ADIPO-IR, adipose tissue insulin resistance measured by palmitate, plasma lipids, TNF, and IL-6 concentrations. There were several significant univariate correlations between metabolic parameters to IL-6 and ATM per 100 adipocytes, but not ATM per gram tissue; adipocyte size was a confounding variable. We used matching strategies and multivariate regression analyses to investigate the relationships between ATM and inflammatory/metabolic parameters independent of adipocyte size. Matching approaches revealed that the groups discordant for CD206 but concordant for adipocyte size had significantly different fasting insulin and IL-6 concentrations. However, groups discordant for adipocyte size but concordent for ATM differeded in that visceral fat, plasma triglyceride, glucose, and TNF concentrations were greater in those with large adipocytes. Multivariate regression analysis indicated that indexes of insulin resistance and fasting triglycerides were predicted by body composition; the predictive value of ATM per 100 adipocytes or per gram tissue was variable between males and females. We conclude that the relationship between ATM burden and metabolic/inflammatory variables is confounded by adipocyte size/body composition and that ATM do not predict insulin resistance, systemic inflammation, or dyslipidemia. ATM may primarily play a role in tissue remodeling rather than in metabolic pathology.


Assuntos
Tecido Adiposo/patologia , Inflamação/patologia , Resistência à Insulina/fisiologia , Macrófagos/patologia , Gordura Abdominal/química , Adipócitos/patologia , Adulto , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Composição Corporal , Índice de Massa Corporal , Feminino , Humanos , Lectinas Tipo C/análise , Receptores de Lipopolissacarídeos/análise , Masculino , Lectinas de Ligação a Manose/análise , Pessoa de Meia-Idade , Obesidade/patologia , Receptores de Superfície Celular/análise , Gordura Subcutânea/química
10.
Am J Pathol ; 190(9): 1909-1920, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32533926

RESUMO

Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.


Assuntos
Adipócitos/patologia , Fibroblastos/patologia , Osteoartrite/patologia , Tecido Adiposo/patologia , Animais , Linhagem da Célula , Articulação do Joelho/patologia , Camundongos , Camundongos Transgênicos , Células-Tronco
11.
Leukemia ; 34(9): 2305-2316, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32474572

RESUMO

The bone marrow is home to well-balanced normal hematopoiesis, but also the stage of leukemia's crime. Marrow adipose tissue (MAT) is a unique and versatile component of the bone marrow niche. While the importance of MAT for bone health has long been recognized, its complex role in hematopoiesis has only recently gained attention. In this review article we summarize recent conceptual advances in the field of MAT research and how these developments impact our understanding of MAT regulation of hematopoiesis. Elucidating routes of interaction and regulation between MAT and cells of the hematopoietic system are essential to pinpoint vulnerable processes resulting in malignant transformation. The concept of white adipose tissue contributing to cancer development and progression on the cellular, metabolic, and systemic level is generally accepted. The role of MAT in malignant hematopoiesis, however, is controversial. MAT is very sensitive to changes in the patient's metabolic status hampering a clear definition of its role in different clinical situations. Here, we discuss future directions for leukemia research in the context of metabolism-induced modifications of MAT and other adipose tissues and how this might impact on leukemia cell survival, proliferation, and antileukemic therapy.


Assuntos
Adipócitos/patologia , Hematopoese , Leucemia/patologia , Doença Aguda , Animais , Humanos , Microambiente Tumoral
12.
PLoS One ; 15(5): e0233152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453755

RESUMO

Obesity is associated with significantly higher mortality rates, and excess adipose tissue is involved in respective pathologies. Here we established a human adipose tissue slice cultures (HATSC) model ex vivo. HATSC match the in vivo cell composition of human adipose tissue with, among others, mature adipocytes, mesenchymal stem cells as well as stroma tissue and immune cells. This is a new method, optimized for live imaging, to study adipose tissue and cell-based mechanisms of obesity in particular. HATSC survival was tested by means of conventional and immunofluorescence histological techniques, functional analyses and live imaging. Surgery-derived tissue was cut with a tissue chopper in 500 µm sections and transferred onto membranes building an air-liquid interface. HATSC were cultured in six-well plates filled with Dulbecco's Modified Eagle's Medium (DMEM), insulin, transferrin, and selenium, both with and without serum. After 0, 1, 7 and 14 days in vitro, slices were fixated and analyzed by morphology and Perilipin A for tissue viability. Immunofluorescent staining against IBA1, CD68 and Ki67 was performed to determine macrophage survival and proliferation. These experiments showed preservation of adipose tissue as well as survival and proliferation of monocytes and stroma tissue for at least 14 days in vitro even in the absence of serum. The physiological capabilities of adipocytes were functionally tested by insulin stimulation and measurement of Phospho-Akt on day 7 and 14 in vitro. Viability was further confirmed by live imaging using Calcein-AM (viable cells) and propidium iodide (apoptosis/necrosis). In conclusion, HATSC have been successfully established by preserving the monovacuolar form of adipocytes and surrounding macrophages and connective tissue. This model allows further analysis of mature human adipose tissue biology ex vivo.


Assuntos
Adipócitos , Tecido Adiposo , Modelos Biológicos , Obesidade , Técnicas de Cultura de Tecidos , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adolescente , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Sobrevivência Celular , Feminino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia
13.
Obesity (Silver Spring) ; 28(6): 1129-1140, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352645

RESUMO

OBJECTIVE: The relationship between adipocyte size and ad libitum energy intake has not been previously examined. This study hypothesized an inverse relationship between adipocyte size and daily energy intake (DEI). METHODS: Seventy healthy adults (39 men and 31 women; BMI 30.0 [SD 6.3]) underwent dual-energy x-ray absorptiometry and subcutaneous fat biopsies from the abdomen and thigh. Osmium-fixed adipocytes were sized with a Coulter counter. Volunteers self-selected food from a vending machine paradigm as the only source of energy intake over 3 days as inpatients. Volunteers also had 24-hour respiratory quotient (RQ) measured in a whole-room indirect calorimeter. RESULTS: In women, the large cell peak diameter of the thigh depot was greater than that of the abdominal depot (Δ = +15.8 µm; P < 0.0001). In women, thigh peak diameter was inversely associated with DEI (ß = -264.7 kcal/d per 10-µm difference; P = 0.03) after adjusting for demographics and body composition. The thigh peak diameter in women was associated with 24-hour RQ (r = -0.47, P = 0.04) after adjusting for demographics, body composition, and 24-hour energy balance. These associations did not extend to men or the abdominal depot. CONCLUSIONS: In women, thigh adipocyte size was associated with reduced DEI and 24-hour RQ, indicating a special role for thigh fat in women. This depot-specific sexual dimorphism indicates common regulation of energy intake and adipocyte size in the thigh region of women.


Assuntos
Adipócitos/patologia , Composição Corporal/fisiologia , Ingestão de Energia/fisiologia , Coxa da Perna/fisiopatologia , Adulto , Idoso , Metabolismo Energético/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Taxa Respiratória , Saúde da Mulher , Adulto Jovem
14.
Biochem Pharmacol ; 175: 113905, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32169417

RESUMO

The aryl hydrocarbon receptor (AHR) has been characterized as multifunctional, ligand-activated transcription factor. Recently, evidence has been obtained that AHR is involved in NAD+ and energy homeostasis in cooperation with NAD+-consuming enzymes including CD38, TiPARP and sirtuins. AHR and CD38 may adversely or beneficially modulate nonalcoholic fatty liver disease (NAFLD) which is associated with obesity, a worldwide major health problem. Although nutritional status and lifestyle are the major factors involved in the prevalence of obesity and NAFLD, modulation of AHR and CD38 has been demonstrated to provide therapeutic options. For example, inhibition of hepatic CD38 and activation of AHR, e.g., by dietary flavonoids may beneficially affect NAFLD. In addition, NAFLD-associated decrease of NAD+ may be restored by administration of the NAD+ precursor nicotinamide riboside.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , NAD/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , ADP-Ribosil Ciclase 1/genética , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Humanos , Fígado/metabolismo , Fígado/patologia , Glicoproteínas de Membrana/genética , NAD/genética , Hepatopatia Gordurosa não Alcoólica/genética , Receptores de Hidrocarboneto Arílico/genética
15.
Arterioscler Thromb Vasc Biol ; 40(5): 1094-1109, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32188271

RESUMO

Adipose tissues are present at multiple locations in the body. Most blood vessels are surrounded with adipose tissue which is referred to as perivascular adipose tissue (PVAT). Similarly to adipose tissues at other locations, PVAT harbors many types of cells which produce and secrete adipokines and other undetermined factors which locally modulate PVAT metabolism and vascular function. Uncoupling protein-1, which is considered as a brown fat marker, is also expressed in PVAT of rodents and humans. Thus, compared with other adipose tissues in the visceral area, PVAT displays brown-like characteristics. PVAT shows a distinct function in the cardiovascular system compared with adipose tissues in other depots which are not adjacent to the vascular tree. Growing and extensive studies have demonstrated that presence of normal PVAT is required to maintain the vasculature in a functional status. However, excessive accumulation of dysfunctional PVAT leads to vascular disorders, partially through alteration of its secretome which, in turn, affects vascular smooth muscle cells and endothelial cells. In this review, we highlight the cross talk between PVAT and vascular smooth muscle cells and its roles in vascular remodeling and blood pressure regulation.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Células Endoteliais/metabolismo , Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Obesidade/metabolismo , Comunicação Parácrina , Adipócitos/patologia , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Animais , Pressão Sanguínea , Células Endoteliais/patologia , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Obesidade/epidemiologia , Obesidade/patologia , Obesidade/fisiopatologia , Fenótipo , Fatores de Risco , Transdução de Sinais , Remodelação Vascular
16.
J Clin Neurosci ; 75: 139-148, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32169364

RESUMO

The multifidus muscle morphology and its relation to the function of patients with degenerative lumbar spinal stenosis (DLSS) remains unclear. This study aimed to investigate the multifidus muscle morphology in patients with DLSS and to determine its relations to the patients function. Sixty-two patients with single-segment DLSS at L4-5 and sixty control patients with non-spinal-derived low back pain were retrospectively enrolled and further matched based on propensity scores. The Oswestry Disability Index (ODI) and bodily pain using the Short-Form Health Survey were evaluated. The cross-sectional area (CSA), CSA of fatty free (CSAF), and fatty infiltration rate [FIR; i.e., (1- CSAF/CSA) × 100%] of the multifidus muscle were measured on magnetic resonance images using ImageJ software. Adjustment for confounders was performed using generalized linear models. The FIR at L5-S1 in controls was statistically significant but slightly less than the DLSS group. The between-groups difference was 5% (p < 0.001), and 2.8% (p = 0.036) in the complete and matching cohorts, respectively, after adjustment. Statistically significant differences were not observed in other multifidus muscle parameters between the groups. FIR > 20% at L5-S1 was independently associated with ODI ≥ 41 in patients with DLSS [Retaining demography as control block or not, Odds ratio (OR) = 8.4, p = 0.023; OR = 12.3, p = 0.030]. The multifidus muscle at L5-S1 demonstrated slightly greater fatty infiltration in patients with L4-5 single-segment DLSS than controls. Significant fatty infiltration in the multifidus muscle at L5-S1 may be correlated with poor function in patients with L4-5 single-segment DLSS.


Assuntos
Músculos Paraespinais/fisiopatologia , Estenose Espinal/fisiopatologia , Adipócitos/patologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Dor Lombar/patologia , Vértebras Lombares/patologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Músculos Paraespinais/diagnóstico por imagem , Músculos Paraespinais/patologia , Pontuação de Propensão , Estudos Retrospectivos , Estenose Espinal/patologia
17.
Acta Orthop Traumatol Turc ; 54(1): 59-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32175898

RESUMO

OBJECTIVE: The aim of this study was to investigate the immunohistochemical stain profiling of adipocytic tumors. METHODS: From our archive files between the years of 2012-2018, excised, formalin-fixed and paraffin-embedded adipocytic tumors were retrospectively screened and 61 subjects were selected. The gender, age, tumor location and tumor diameter were evaluated. The cases were investigated in terms of p16, CD34, MDM2 expression and clinicopathological information. RESULTS: Of the 61 patients included in the study, we found that 2 had hibernoma, 4 had lipoblastoma, 14 had spindle cell lipoma (SCL), 10 had lipoma, 20 had atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDL), and 11 had dedifferentiated liposarcoma (DDL). In terms of diameter, ALT/WDL and DDL were significantly different from the others (p=0.001, p=0.001, respectively). There was a significant difference between the groups according to the location (p=0.001). 35% (7/20) of ALT/WDLs were in the lower extremities (thighs) and 35% (7/20) were located in the retroperitoneal region. 70% of DDLs (7/11) were located in the retroperitoneum. When CD34 expression was evaluated among the groups, a significant difference was observed (p=0.001). CD34 was positive in 92.9% of SCL cases. p16 immunoreactivity was significantly different between the groups (p=0.001). p16 expression was observed in 50.5% of ALT / WDL cases and 79% of DDL cases. CONCLUSION: p16 and CD34 expression are valuable in the differential diagnosis of lipomatous tumors when radiological and clinical considerations do not help to differential diagnosis of adipocytic tumors. LEVEL OF EVIDENCE: Level IV, Therapeutic Study.


Assuntos
Antígenos CD34/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Lipoma , Lipossarcoma , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Adipócitos/patologia , Adulto , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Lipoma/metabolismo , Lipoma/patologia , Lipossarcoma/classificação , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
18.
Br J Radiol ; 93(1110): 20190794, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32105502

RESUMO

OBJECTIVE: To investigate the specificity, clinical implication and prognostic value of MRI adipocytic maturation (MAM) in myxoid/round cells liposarcomas (MRC-LPS) treated with neoadjuvant chemotherapy (NAC). METHODS: Of the 89 patients diagnosed with MRC-LPS at our sarcoma reference center between 2008 and 2018, 28 were included as they were treated with NAC, surgery and radiotherapy. All patients underwent contrast-enhanced MRIs at baseline and late evaluation. A control cohort of 13 high-grade pleomorphic and dedifferentiated LPS with same inclusion criteria was used to evaluate the specificity of MAM in MRC-LPS. Two radiologists analyzed the occurrence of MAM, changes in the tumor architecture, shape and surrounding tissues during NAC. Pathological features of tumor samples were reviewed and correlated with MRI. Metastatic relapse-free survival was estimated with Kaplan-Meier curves and Cox models. Associations between prognostic T1-based delta-radiomics features and MAM were investigated with Student t-test. RESULTS: MAM was more frequent in MRC-LPS (p = 0.045) and not specific of any type of chemotherapy (p = 0.7). Regarding MRC-LPS, 14 out of 28 patients (50%) demonstrated MAM. Eight patients showed metastatic relapses. MAM was not associated with metastatic relapse-free survival (p = 0.9). MAM correlated strongly with the percentage of histological adipocytic differentiation on surgical specimen (p < 0.001), which still expressed the tumor marker NY-ESO-1. None of the prognostic T1-based delta-radiomics features was associated with MAM. CONCLUSION: MAM seems a neutral event during NAC. ADVANCES IN KNOWLEDGE: MAM predominated in MRC-LPS and was not specific of a type of chemotherapy. Occurrence of MAM was not associated with better patients' metastasis free survival.


Assuntos
Adipócitos/patologia , Diferenciação Celular , Lipossarcoma Mixoide/diagnóstico por imagem , Lipossarcoma Mixoide/patologia , Imagem por Ressonância Magnética , Adipócitos/efeitos dos fármacos , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Meios de Contraste , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipossarcoma Mixoide/tratamento farmacológico , Lipossarcoma Mixoide/terapia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Sensibilidade e Especificidade , Carga Tumoral
19.
Nat Commun ; 11(1): 719, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024826

RESUMO

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload.


Assuntos
Tecido Adiposo/metabolismo , Vesículas Extracelulares/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Índice de Massa Corporal , Dieta Hiperlipídica/efeitos adversos , Vesículas Extracelulares/genética , Farnesiltranstransferase/genética , Humanos , Lipogênese , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , Complexos Multienzimáticos/genética , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas rab27 de Ligação ao GTP/genética , Proteínas rab27 de Ligação ao GTP/metabolismo
20.
Biochem Biophys Res Commun ; 525(2): 433-439, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32102755

RESUMO

Bone marrow adipose tissue (BMAT) has recently been found to induce osteoclastogenesis by secreting RANKL. Although Type 1 diabetes mellitus (T1DM) has been reported to be associated with increased BMAT and bone loss, little is known about the relationship between BMAT and osteoclasts in T1DM. We studied the role of BMAT in the alterations of osteoclast activities in early-stage T1DM, by using a streptozotocin-induced T1DM mouse model. Our results showed that osteoclast activity was enhanced in the long bones of T1DM mice, accompanied by increased protein expression of RANKL. However, RANKL mRNA levels in bone tissues of T1DM mice remained unchanged. Meanwhile, we found that BMAT was significantly increased in the long bones of T1DM mice, and both mRNA and protein levels of RANKL were elevated in the diabetic BMAT. More importantly, RANKL protein was mainly expressed on the cell membranes of the increased adipocytes, most of which were located next to the metaphyseal region. These results suggest that the enhanced bone resorption in early-stage diabetic mice is induced by RANKL derived from BMAT rather than the bone tissue itself.


Assuntos
Adipócitos/patologia , Reabsorção Óssea/patologia , Diabetes Mellitus Tipo 1/patologia , Ligante RANK/metabolismo , Adipócitos/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/análise
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