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1.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/metabolismo
2.
Nat Commun ; 11(1): 4718, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948777

RESUMO

Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Linfócitos/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Adipócitos/metabolismo , Adolescente , Adulto , Idoso , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Glucose/metabolismo , Homeostase , Humanos , Imunidade Inata , Resistência à Insulina , Interleucina-33/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Membro 25 de Receptores de Fatores de Necrose Tumoral/uso terapêutico , Adulto Jovem
3.
Elife ; 92020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32930095

RESUMO

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.


Assuntos
Infecções por Coronavirus/microbiologia , Diabetes Mellitus/microbiologia , Obesidade/microbiologia , Pneumonia Viral/microbiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/microbiologia , Complicações do Diabetes/virologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Regulação para Baixo , Interações entre Hospedeiro e Microrganismos , Humanos , Interações Microbianas , Obesidade/metabolismo , Obesidade/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Carga Viral
4.
Internist (Berl) ; 61(10): 1063-1075, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32930809

RESUMO

Lipodystrophy (LD) syndromes are a group of rare and heterogeneous diseases characterized by a congenital deficiency or acquired loss of adipose tissue. Due to the resulting disorder of metabolism, sometimes severe sequelae can develop, such as hypertriglyceridemia, marked insulin resistance and early manifestation of type 2 diabetes, recurrent pancreatitis, fatty liver disease and liver fibrosis. Lipodystrophies are clinically recognizable due to the complete lack of subcutaneous adipose tissue or a conspicuous pattern of the distribution of body fat. Acanthosis nigricans in slimly built persons, a high fasting triglyceride level and elevated concentrations of liver enzymes as well as a positive history of pancreatitis can be indications of LD.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Lipoatrófica , Resistência à Insulina , Lipodistrofia , Tecido Adiposo/patologia , Diabetes Mellitus Tipo 2 , Humanos , Lipodistrofia/diagnóstico , Lipodistrofia/etiologia , Lipodistrofia/metabolismo , Lipodistrofia/terapia , Doenças Raras
5.
Sheng Wu Gong Cheng Xue Bao ; 36(8): 1504-1514, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32924349

RESUMO

MicroRNA (miRNA) is a type of highly conserved nucleotide sequence composed of 18 to 25 nucleotides, which can specifically bind to the 3'-noncoding regions of mRNA, and then play a negative regulatory role in degrading mRNA or inhibiting translation. Long non-coding RNA (lncRNA) is a type of nucleotide sequence that exceeds 200 nucleotides in length and cannot encode proteins or can only encode protein peptides. It regulates gene expression at the levels of epigenetic, transcriptional and post-transcriptional. As an important energy storage organ, fat plays an important role in regulating the energy balance of animals, and is closely related to meat production traits such as meat production and meat quality. And the disorder of fat function can lead to hyperlipidemia, type 2 diabetes and a series of cardiovascular diseases, so the molecular regulation mechanism of animal fat deposition has attracted more attention. In recent years, more and more studies have found that miRNA and lncRNA play a crucial role in animal fat deposition. We review here the current research progresses in the role of miRNA and lncRNA in animal fat deposition, to provide theoretical guidance and new ideas for further revealing the molecular regulation mechanism of animal fat deposition.


Assuntos
Tecido Adiposo , MicroRNAs , RNA Longo não Codificante , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2 , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro
6.
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
7.
Arch Environ Contam Toxicol ; 79(2): 167-176, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32601753

RESUMO

Blubber taken from ringed seals (Pusa hispida) during a subsistence hunt at Ulukhaktok, NT (formerly Holman, NWT) at intervals between 2002 and 2015 was analysed for polybrominated diphenyl ether (PBDE) congeners. Results from these analyses were combined with others previously published to yield a data set of 18 tri- to hepta-substituted PBDE congeners in 102 animals sampled over a span of 19 year (females) and 34 year (males). In females, mean total PBDE concentrations increased between 1996 and 2015 by approximately 50%, from 1940 to 2780 pg/g wet wt., although not significantly so (p > 0.05) by one-way ANOVA. In males, concentrations ranged from 376 to 6470 pg/g wet wt. between 1981 and 2015 (p < 0.05). In males, the most rapid increase in PBDE concentrations occurred before 2000, but between 2002 and 2015 mean total PBDE concentrations increased by a further 50%. ANCOVA showed PBDE concentrations in females to be correlated (p < 0.05) with sampling year but not with age or condition (as measured by blubber thickness); in males, PBDE concentrations were strongly correlated (p < 0.01) with year, age and condition. The relative proportions of tetra-bromo- congeners declined weakly in both sexes over the sampling period, with a compensatory increase in penta-bromo-congener distribution. Overall, the results show no evidence yet of a decline in PBDE concentrations in western Arctic ringed seals in response to voluntary and regulated restrictions on PBDE use in the early 2000s.


Assuntos
Tecido Adiposo/metabolismo , Monitoramento Ambiental , Éteres Difenil Halogenados/metabolismo , Focas Verdadeiras/metabolismo , Animais , Regiões Árticas , Canadá , Feminino , Éteres Difenil Halogenados/análise , Masculino
8.
PLoS One ; 15(7): e0235632, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628720

RESUMO

Emerging evidence suggests that parents' preconception exposures may influence offspring health. We aimed to investigate maternal and paternal smoking onset in specific time windows in relation to offspring body mass index (BMI) and fat mass index (FMI). We investigated fathers (n = 2111) and mothers (n = 2569) aged 39-65 years, of the population based RHINE and ECRHS studies, and their offspring aged 18-49 years (n = 6487, mean age 29.6 years) who participated in the RHINESSA study. BMI was calculated from self-reported height and weight, and FMI was estimated from bioelectrical impedance measures in a subsample. Associations with parental smoking were analysed with generalized linear regression adjusting for parental education and clustering by study centre and family. Interactions between offspring sex were analysed, as was mediation by parental pack years, parental BMI, offspring smoking and offspring birthweight. Fathers' smoking onset before conception of the offspring (onset ≥15 years) was associated with higher BMI in the offspring when adult (ß 0.551, 95%CI: 0.174-0.929, p = 0.004). Mothers' preconception and postnatal smoking onset was associated with higher offspring BMI (onset <15 years: ß1.161, 95%CI 0.378-1.944; onset ≥15 years: ß0.720, 95%CI 0.293-1.147; onset after offspring birth: ß2.257, 95%CI 1.220-3.294). However, mediation analysis indicated that these effects were fully mediated by parents' postnatal pack years, and partially mediated by parents' BMI and offspring smoking. Regarding FMI, sons of smoking fathers also had higher fat mass (onset <15 years ß1.604, 95%CI 0.269-2.939; onset ≥15 years ß2.590, 95%CI 0.544-4.636; and onset after birth ß2.736, 95%CI 0.621-4.851). There was no association between maternal smoking and offspring fat mass. We found that parents' smoking before conception was associated with higher BMI in offspring when they reached adulthood, but that these effects were mediated through parents' pack years, suggesting that cumulative smoking exposure during offspring's childhood may elicit long lasting effects on offspring BMI.


Assuntos
Tecido Adiposo/metabolismo , Crianças Adultas , Índice de Massa Corporal , Fertilização , Pais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fumar/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez
9.
Gene ; 760: 144998, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32717304

RESUMO

The life cycle of holometabolous insects involves different stages and cathepsin plays an important role in insect metamorphosis. In the present study, we investigated the function of Bombyx mori cathepsin-L (Bm-CatL) during metamorphosis and analyzed their role in programmed cell death (PCD) of the fat body. The results showed that knockdown of Bm-CatL by RNA interference led to abnormal pupation and a delay in fat body degradation during metamorphosis. Furthermore, PCD inhibition was observed in the fat body after downregulation of Bm-CatL. To confirm this finding, PCD was induced in Bombyx mori embryonic (BmE) cells by ultraviolet ray irradiation. We found that the PCD of BmE cells was weakened after knocking down Bm-CatL. Moreover, overexpression of Bm-CatL in cells promoted PCD. Overall, our results showed that Bm-CatL is involved in the degradation of internal tissues and promotes the PCD of cells involved in the pupation of silkworms. Thus, this study provides us with a better understanding for function of cathepsin-L during metamorphosis.


Assuntos
Bombyx/fisiologia , Catepsina L/metabolismo , Tecido Adiposo/metabolismo , Animais , Apoptose/fisiologia , Bombyx/genética , Bombyx/metabolismo , Corpo Adiposo/metabolismo , Proteínas de Insetos/metabolismo , Metamorfose Biológica , Interferência de RNA
10.
BMC Evol Biol ; 20(1): 93, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727355

RESUMO

BACKGROUND: The adaptive significance of phenotypic changes elicited by environmental conditions experienced early in life has long attracted attention in evolutionary biology. In this study, we used Drosophila melanogaster to test whether the developmental diet produces phenotypes better adapted to cope with similar nutritional conditions later in life. To discriminate among competing hypotheses on the underlying nature of developmental plasticity, we employed a full factorial design with several developmental and adult diets. Specifically, we examined the effects of early- and late-life diets (by varying their yeast and sugar contents) on reproductive fitness and on the amount of energy reserves (fat and glycogen) in two wild-caught populations. RESULTS: We found that individuals that had developed on either low-yeast or high-sugar diet showed decreased reproductive performance regardless of their adult nutritional environment. The lower reproductive fitness might be caused by smaller body size and reduced ovariole number. Overall, these results are consistent with the silver spoon concept, which posits that development in a suboptimal environment negatively affects fitness-associated traits. On the other hand, the higher amount of energy reserves (fat) in individuals that had developed in a suboptimal environment might represent either an adaptive response or a side-effect of compensatory feeding. CONCLUSION: Our findings suggest that the observed differences in the adult physiology induced by early-life diet likely result from inevitable and general effects of nutrition on the development of reproductive and metabolic organs, rather than from adaptive mechanisms.


Assuntos
Dieta , Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiologia , Tecido Adiposo/metabolismo , Animais , Tamanho Corporal , Metabolismo Energético , Feminino , Fertilidade , Aptidão Genética , Glicogênio/metabolismo , Masculino , Fenótipo , Reprodução , Açúcares/análise , Leveduras
11.
Clín. investig. arterioscler. (Ed. impr.) ; 32(3): 129-134, mayo-jun. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-193359

RESUMO

La enfermedad renal crónica representa un verdadero estado inflamatorio y está relacionada con múltiples factores de riesgo cardiovascular. La enfermedad arterial coronaria es una de sus principales complicaciones y usualmente ha sido asociada con factores de riesgo cardiovascular no clásicos o propios de pacientes urémicos como las alteraciones del metabolismo del calcio y el fósforo, entre otros. Evidencia clínica reciente muestra que el depósito de grasa órgano específico, como el tejido adiposo epicárdico, es un factor de riesgo adicional a tener en cuenta en el momento de la evaluación de riesgo cardiovascular en la población general y en los pacientes renales. La interacción directa de este tejido con los vasos coronarios y la consecuente mediación de sustancias proaterogénicas generan un proceso local que termina en la producción de daño endotelial. Aunque la población de enfermos renales ha sido evaluada escasamente, estudios futuros determinarán con precisión si un incremento en la adiposidad epicárdica está verdaderamente asociado a la morbimortalidad cardiovascular en este grupo de riesgo


Chronic kidney disease represents a true inflammatory state, and is related to multiple cardiovascular risk factors. Coronary artery disease is the major complication, and has usually been associated with non-classical or uraemic related factors that include the disturbance of calcium and phosphorus metabolism, among others. Recent clinical evidence shows that specific body fat deposition like epicardial adipose tissue is an additional factor to consider when evaluating cardiovascular risk in the general population and kidney patients. Direct interaction of this tissue and coronary vessels with consequent mediation of pro-atherogenic substances have a local process ending in endothelial damage. Although the population of renal patients has been poorly evaluated, future studies should determine precisely whether an increase in epicardial fat is truly associated with cardiovascular morbidity and mortality in this risk group


Assuntos
Humanos , Tecido Adiposo , Tecido Adiposo/metabolismo , Síndrome Metabólica/complicações , Insuficiência Renal Crônica/complicações , Doença da Artéria Coronariana/complicações , Gordura Subcutânea , Fatores de Risco , Cálcio/metabolismo , Fósforo/metabolismo , Pericárdio/fisiopatologia , Pericárdio/diagnóstico por imagem , Obesidade/fisiopatologia
12.
PLoS One ; 15(6): e0232972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32512581

RESUMO

Various dietary fibers are considered to prevent obesity by modulating the gut microbiota. Cordyceps sinensis polysaccharide (CSP) is a soluble dietary fiber known to have protective effects against obesity and related diseases, but whether these effects induce any side effects remains unknown. The function and safety of CSP were tested in high-fat diet (HFD)-feding C57BL/6J mice. The results revealed that even though CSP supplementation could prevent an increase in body weight, it aggravated liver fibrosis and steatosis as evidenced by increased inflammation, lipid metabolism markers, insulin resistance (IR) and alanine aminotransferase (ALT) in HFD-induced obesity. 16S rDNA gene sequencing was used to analyze the gut microbiota composition, and the relative abundance of the Actinobacteria phylum, including the Olsenella genus, was significantly higher in CSP-treated mice than in HFD-fed mice. CSP supplementation may increase the proportion of Actinobacteria, which can degrade CSP. The high level of Actinobacteria aggravated the disorder of the intestinal flora and contributed to the progression from obesity to nonalcoholic steatohepatitis (NASH) and related diseases.


Assuntos
Cordyceps , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/administração & dosagem , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polissacarídeos/administração & dosagem , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Peso Corporal , Cordyceps/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Resistência à Insulina , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Polissacarídeos/isolamento & purificação
13.
J Frailty Aging ; 9(3): 134-138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32588026

RESUMO

BACKGROUND: High levels of intramuscular adipose tissue and low levels of capillarization are both predicative of low muscle and mobility function in older adults, however little is known about their relationship. OBJECTIVES: The purpose of this study was to examine the relationship of intramuscular adipose tissue and capillarization in older adults. SETTING: An outpatient medical center. PARTICIPANTS: Forty-seven sedentary adults (age 59.9 ± 1.0 years, BMI 32.0 ± 0.7 kg/m2, VO2max 22.4 ± 0.7 ml/kg/min); Measurements: All participants underwent CT scans to determine intramuscular adipose tissue and muscle biopsies to determine capillarization in the mid-thigh. A step-wise hierarchical linear regression analysis was used to examine the contributions of age, sex, race, body mass index, 2-hour postprandial glucose, VO2max, and muscle capillarization, to the variability in intramuscular adipose tissue. RESULTS: The predictors as a group accounted for 38.1% of the variance in intramuscular adipose tissue, with body mass index and capillarization each significantly contributing to the final model (P<0.001). The part correlation of body mass index with intramuscular adipose tissue was r = 0.47, and the part correlation of capillarization with intramuscular adipose tissue was r = 0.39, indicating that body mass index and capillarization explained 22.1%, and 15.2% of the variance in intramuscular adipose tissue. CONCLUSIONS: While increased muscle capillarization is typically thought of as a positive development, in some clinical conditions, such as tendinopathies, an increase in capillarization is part of the pathological process related to expansion of the extracellular matrix and fibrosis. This may also be an explanation for the surprising finding that high capillarization is related to high levels of intramuscular adipose tissue. Future studies are necessary to determine the relationship of changes in both capillarization and intramuscular adipose tissue after interventions, such as exercise.


Assuntos
Tecido Adiposo/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Índice de Massa Corporal , Capilares/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coxa da Perna/irrigação sanguínea
14.
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
15.
Nat Commun ; 11(1): 2922, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523103

RESUMO

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis.


Assuntos
Tecido Adiposo/metabolismo , Eosinófilos/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Transdução de Sinais/fisiologia , Adiposidade/genética , Adiposidade/fisiologia , Animais , Células COS , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Citometria de Fluxo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Obesidade/metabolismo , Transdução de Sinais/genética , Software
16.
Nat Commun ; 11(1): 3085, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555187

RESUMO

Orthogonal tools for controlling protein function by post-translational modifications open up new possibilities for protein circuit engineering in synthetic biology. Phosphoregulation is a key mechanism of signal processing in all kingdoms of life, but tools to control the involved processes are very limited. Here, we repurpose components of bacterial two-component systems (TCSs) for chemically induced phosphotransfer in mammalian cells. TCSs are the most abundant multi-component signal-processing units in bacteria, but are not found in the animal kingdom. The presented phosphoregulated orthogonal signal transduction (POST) system uses induced nanobody dimerization to regulate the trans-autophosphorylation activity of engineered histidine kinases. Engineered response regulators use the phosphohistidine residue as a substrate to autophosphorylate an aspartate residue, inducing their own homodimerization. We verify this approach by demonstrating control of gene expression with engineered, dimerization-dependent transcription factors and propose a phosphoregulated relay system of protein dimerization as a basic building block for next-generation protein circuits.


Assuntos
Histidina Quinase/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Feminino , Regulação da Expressão Gênica , Células HEK293 , Histidina/química , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Nanotecnologia , Fosforilação , Domínios Proteicos , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Biologia Sintética , Fatores de Transcrição/metabolismo
17.
PLoS One ; 15(6): e0228521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544198

RESUMO

BACKGROUND AND AIMS: Adipose tissue plays a pivotal role in storing excess fat and its composition reflects the history of person's lifestyle and metabolic health. Broad profiling of lipids with mass spectrometry has potential for uncovering new knowledge on the pathology of obesity, metabolic syndrome, diabetes and other related conditions. Here, we developed a lipidomic method for analyzing human subcutaneous adipose biopsies. We applied the method to four body areas to understand the differences in lipid composition between these areas. MATERIALS AND METHODS: Adipose tissue biopsies from 10 participants were analyzed using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The sample preparation optimization included the optimization of the lipid extraction, the sample amount and the sample dilution factor to detect lipids in an appropriate concentration range. Lipidomic analyses were performed for adipose tissue collected from the abdomen, breast, thigh and lower back. Differences in lipid levels between tissues were visualized with heatmaps. RESULTS: Lipidomic analysis on human adipose biopsies lead to the identification of 186lipids in 2 mg of sample. Technical variation of the lipid-class specific internal standards were below 5%, thus indicating acceptable repeatability. Triacylglycerols were highly represented in the adipose tissue samples, and lipids from 13 lipid classes were identified. Long polyunsaturated triacylglycerols in higher levels in thigh (q<0.05), when compared with the abdomen, breast and lower back, indicating that the lipidome was area-specific. CONCLUSION: The method presented here is suitable for the analysis of lipid profiles in 2 mg of adipose tissue. The amount of fat across the body is important for health but we argue that also the distribution and the particular profile of the lipidome may be relevant for metabolic outcomes. We suggest that the method presented in this paper could be useful for detecting such aberrations.


Assuntos
Tecido Adiposo/metabolismo , Lipidômica , Tecido Adiposo/patologia , Biópsia , Humanos , Especificidade de Órgãos
18.
Eur J Endocrinol ; 183(1): 51-61, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32503004

RESUMO

Objective: We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. Research design and methods: Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). Results: Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. Conclusion: Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.


Assuntos
Tecido Adiposo/metabolismo , Terapia por Exercício/métodos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/terapia , Resistência à Insulina , Obesidade/metabolismo , Obesidade/terapia , Adiposidade , Adulto , Glicemia , Feminino , Humanos , Hiperinsulinismo/complicações , Obesidade/complicações , África do Sul , Resultado do Tratamento , Adulto Jovem
19.
Obesity (Silver Spring) ; 28(7): 1245-1253, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32475048

RESUMO

OBJECTIVE: This study aimed to investigate the effect of exercise intensity on visceral adipose tissue (VAT) and liver fat reduction in patients with coronary artery disease (CAD) over 3 months and the maintenance of improvements over 12 months. METHODS: Forty-two participants with CAD were randomized to three sessions/week of either 4 × 4-minute high-intensity interval training (HIIT) or 40 minutes of usual care moderate-intensity continuous training (MICT) for a 4-week supervised cardiac rehabilitation program, followed by three home-based sessions/week for 11 months. Liver fat (as intrahepatic lipid) and VAT were measured via magnetic resonance techniques. Data are mean change (95% CI). RESULTS: HIIT and MICT significantly reduced VAT over 3 months (-350 [-548 to -153] cm3 vs. -456 [-634 to -278] cm3 ; time × group effect: P = 0.421), with further improvement over 12 months (-545 [-818 to -271] cm3 vs. -521 [-784 to -258] cm3 ; time × group effect: P = 0.577) and no differences between groups. Both groups improved liver fat over 3 months, with HIIT tending to show greater reduction than MICT (-2.8% [-4.0% to -1.6%] vs. -1.4% [-2.4% to -0.4%]; time × group effect: P = 0.077). After 12 months, improvements were maintained to a similar degree. Higher exercise intensity predicted liver fat reduction (ß = -0.3 [-0.7 to 0.0]; P = 0.042). CONCLUSIONS: HIIT and MICT reduced VAT over 3 and 12 months. For liver fat, HIIT tended to provide a slightly greater reduction compared with MICT. These findings support HIIT as a beneficial adjunct or alternative to MICT for reducing visceral and liver fat in patients with CAD.


Assuntos
Tecido Adiposo/metabolismo , Reabilitação Cardíaca/métodos , Doença da Artéria Coronariana/terapia , Treinamento Intervalado de Alta Intensidade/métodos , Gordura Intra-Abdominal/patologia , Fígado/metabolismo , Adiposidade/fisiologia , Idoso , Composição Corporal/fisiologia , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Resultado do Tratamento
20.
Obesity (Silver Spring) ; 28(7): 1292-1300, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568462

RESUMO

OBJECTIVE: Lipedema is characterized by pain, fatigue, and excessive adipose tissue and sodium accumulation of the lower extremities. This case-control study aims to determine whether sodium or vascular dysfunction is present in the central nervous system. METHODS: Brain magnetic resonance imaging was performed at 3 T in patients with lipedema (n = 15) and control (n = 18) participants matched for sex, age, race, and BMI. Standard anatomical imaging and intracranial angiography were applied to evaluate brain volume and vasculopathy, respectively; arterial spin labeling and sodium magnetic resonance imaging were applied to quantify cerebral blood flow (CBF) (milliliters per 100 grams of tissue/minute) and brain tissue sodium content (millimoles per liter), respectively. A Mann-Whitney U test (significance criteria P < 0.05) was applied to evaluate group differences. RESULTS: No differences in tissue volume, white matter hyperintensities, intracranial vasculopathy, or tissue sodium content were observed between groups. Gray matter CBF was elevated (P = 0.03) in patients with lipedema (57.2 ± 9.6 mL per 100 g/min) versus control participants (49.8 ± 9.1 mL per 100 g/min). CONCLUSIONS: Findings provide evidence that brain sodium and tissue fractions are similar between patients with lipedema and control participants and that patients with lipedema do not exhibit abnormal radiological indicators of intracranial vasculopathy or ischemic injury. Potential explanations for elevated CBF are discussed in the context of the growing literature on lipedema symptomatology and vascular dysfunction.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Lipedema/metabolismo , Lipedema/fisiopatologia , Sódio/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Química Encefálica/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Lipedema/diagnóstico , Lipedema/psicologia , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Neuroimagem/métodos , Sódio/análise
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