Assuntos
Criocirurgia/efeitos adversos , Insulinas/efeitos adversos , Lipectomia/efeitos adversos , Gordura Subcutânea Abdominal/patologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Idoso , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Hiperplasia , Bombas de Infusão Implantáveis , Insulinas/administração & dosagem , Lipectomia/métodos , Masculino , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/cirurgiaRESUMO
BACKGROUND: Nonsurgical fat reduction procedures using cryolipolysis and radiofrequency are among the most popular noninvasive aesthetic procedures. In a previous study, TransFORM Body Treatment (TFB) with TriHex Technology® (ALASTIN® Skincare) improved the contour and reduced skin laxity following cryolipolysis of the arms. This product is formulated using a combination of peptides and other active ingredients designed to stimulate the autophagic breakdown of lipid droplets and expedite the apoptotic process after fat reduction procedures. AIMS: To assess the changes in abdominal volume after application of TFB for 12 weeks following cryolipolysis and radiofrequency procedures. METHODS: Following abdominal cryolipolysis or radiofrequency therapy, the subjects (N = 15) received TFB product and placebo and were randomly assigned to apply to the right or left sides of the abdomen for 12 weeks. Using 3-dimensional digital imaging analysis, subjects were evaluated at 4, 8, and 12 weeks posttreatment. RESULTS: Topical TFB resulted in increased volume loss, which was greater than that for placebo at weeks 4 (P = .0511), 8 (P = .0238), and 12 (P = .0078), respectively, and statistically significant at weeks 8 and 12. There were no reported adverse events. CONCLUSION: In this study, Topical application of TFB significantly increased adipose volume loss and improved clinical outcomes of nonsurgical fat reduction procedures.
Assuntos
Crioterapia/métodos , Lipectomia/métodos , Obesidade Abdominal/terapia , Peptídeos/administração & dosagem , Terapia por Radiofrequência/métodos , Abdome/diagnóstico por imagem , Administração Cutânea , Adulto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Crioterapia/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imageamento Tridimensional , Lipectomia/efeitos adversos , Pessoa de Meia-Idade , Obesidade Abdominal/diagnóstico , Satisfação do Paciente , Peptídeos/efeitos adversos , Fotografação , Terapia por Radiofrequência/efeitos adversos , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/efeitos da radiação , Resultado do TratamentoRESUMO
BACKGROUND: ATX-101 is approved for submental fat reduction. OBJECTIVE: To characterize the histological effect of ATX-101 injection into subcutaneous fat. METHODS: This Phase 1 open-label study enrolled 14 adults to receive injections of ATX-101 into abdominal fat at varying concentrations (0.5%, 1.0%, 2.0%, or 4.0%), volumes (0.2 or 0.4 mL), spacing (0.7, 1.0, or 1.5 cm), and time points before scheduled abdominoplasty (1, 3, 7, or 28 days). During abdominoplasty, tissue was excised and preserved for histology. RESULTS: All injection paradigms resulted in histological changes confined to the subcutaneous layer, which were more prominent at higher concentrations and independent of volume and spacing. Key features at Day 1 after injection were adipocytolysis, blood vessel injury, neutrophilic inflammation, and lysis of locally present neutrophils. At Day 3, inflammation was reduced versus Day 1, and hemorrhage and lipid lake formation (at higher concentrations) were observed. Day 7 samples exhibited prominent adipocytolysis, mild inflammation, lipid-laden macrophages in the septae, and repair of vascular injury. At Day 28, inflammation was largely resolved and prominent features were septal thickening, neovascularization, and atrophy of fat lobules. CONCLUSION: Subcutaneous injection of ATX-101 induces adipocytolysis and local inflammation with septal thickening and resolution of inflammation by 28 days after injection.
Assuntos
Colagogos e Coleréticos/farmacologia , Técnicas Cosméticas , Ácido Desoxicólico/farmacologia , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/patologia , Adulto , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Fatores de TempoAssuntos
Dióxido de Carbono/administração & dosagem , Sobrepeso/terapia , Dor/diagnóstico , Gordura Subcutânea Abdominal/efeitos dos fármacos , Adulto , Dióxido de Carbono/efeitos adversos , Feminino , Humanos , Injeções Subcutâneas , Dor/etiologia , Medição da Dor , Satisfação do Paciente , Projetos Piloto , Resultado do TratamentoRESUMO
BACKGROUND: The adjunction of autologous platelet-rich plasma (PRP) is emerging as a promising approach to enhance the long-term survival of fat grafting, but there are still insufficient data on its efficacy. The aim of this in vivo study was to assess the effect of the addition of non-activated PRP on fat graft outcome. METHODS: Human adipose tissue mixed with 20% of non-activated PRP was injected under the scalp skin of nude Balb/cAnNRj mice and compared to grafted fat mixed with 20% of saline. The fat graft volume was analyzed by a computed tomography scan until day 90 and immunohistochemistry was then performed to assess adipocyte viability and graft revascularization. RESULTS: At day 90, the volume of fat graft was not enhanced by PRP compared to the saline control group. However, immunohistochemistry showed that PRP significantly increased the fat graft area occupied by intact adipocytes compared to the saline group (72.66% vs. 60.78%, respectively; p < 0.05). Vascularity was also significantly higher in the PRP group compared to the control group (6695 vs. 4244 CD31+ cells/µm2, respectively; p < 0.05). CONCLUSION: The adjunction of non-activated-PRP to fat grafts significantly increased adipocyte viability and tissue vascularity. However, in contrast to other studies adding activated-PRP, non-activated-PRP did not increase residual fat graft volume until day 90. Further studies are therefore needed to understand whether PRP has a positive effect on fat graft volume. As 3D computed tomography scan is a reproducible and precise technique, it should be used to analyze fat graft volume changes over time.
Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Plasma Rico em Plaquetas/metabolismo , Gordura Subcutânea Abdominal/transplante , Animais , Feminino , Humanos , Imageamento Tridimensional , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Gordura Subcutânea Abdominal/diagnóstico por imagem , Gordura Subcutânea Abdominal/efeitos dos fármacos , Tomografia Computadorizada por Raios XRESUMO
Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 µM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 µM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 µM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 µM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed.
Assuntos
Inibidores da Captação Adrenérgica/efeitos adversos , Lipólise , Gordura Subcutânea Abdominal/metabolismo , Tiramina/efeitos adversos , Toxina Adenilato Ciclase/farmacologia , Inibidores da Captação Adrenérgica/química , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Adulto , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feminino , Glicerol/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Cinética , Lipólise/efeitos dos fármacos , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/metabolismo , Procedimentos de Cirurgia Plástica , Gordura Subcutânea Abdominal/citologia , Gordura Subcutânea Abdominal/efeitos dos fármacos , Tiramina/antagonistas & inibidoresRESUMO
BACKGROUND: Noninvasive fat removal is preferred because of decreased downtime and lower perceived risk. It is important to seek new noninvasive fat removal treatments that are both safe and efficacious. OBJECTIVE: To assess the extent to which carboxytherapy, which is the insufflation of carbon dioxide gas into subcutaneous fat, results in reduction of fat volume. METHODS: In this randomized, sham-controlled, split-body study, adults (body mass index, 22-29 kg/m2) were randomized to receive 5 weekly infusions of 1000 cm3 of CO2 to 1 side of the abdomen, and 5 sham treatments to the contralateral side. The primary outcome measures were ultrasound measurement of fat layer thickness and total circumference before and after treatment. RESULTS: A total of 16 participants completed the study. Ultrasound measurement indicated less fat volume on the side treated with carboxytherapy 1 week after the last treatment (P = .011), but the lower fat volume was not maintained at 28 weeks. Total circumference decreased nominally but not significantly at week 5 compared with baseline (P = .0697). Participant body weights did not change over the entire course of the study (P = 1.00). LIMITATIONS: Limitations included modest sample size and some sources of error in the measurement of circumference and fat layer. CONCLUSION: Carboxytherapy provides a transient decrease in subcutaneous fat that may not persist. Treatment is well tolerated.
Assuntos
Contorno Corporal/métodos , Dióxido de Carbono/uso terapêutico , Gordura Subcutânea Abdominal/efeitos dos fármacos , Adiposidade , Adulto , Dióxido de Carbono/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Insuflação , Masculino , Pessoa de Meia-Idade , Recidiva , Falha de Tratamento , UltrassonografiaAssuntos
Contorno Corporal/efeitos adversos , Ácido Desoxicólico/uso terapêutico , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/patologia , Feminino , Humanos , Hiperplasia/tratamento farmacológico , Hiperplasia/etiologia , Hiperplasia/patologia , Pessoa de Meia-IdadeRESUMO
Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male Irak1 null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice (versus WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the Irak1 k/o mice on chow diet, but the Irak1 deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in Irak1 k/o mice in vivo Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from Irak1 k/o mice ex vivo In conclusion, Irak1 deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice.
Assuntos
Intolerância à Glucose/metabolismo , Resistência à Insulina , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Músculo Esquelético/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cruzamentos Genéticos , Dieta com Restrição de Gorduras , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Técnica Clamp de Glucose , Intolerância à Glucose/etiologia , Intolerância à Glucose/fisiopatologia , Intolerância à Glucose/prevenção & controle , Hemizigoto , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Obesidade/etiologia , Obesidade/fisiopatologia , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/enzimologia , Gordura Subcutânea Abdominal/metabolismoRESUMO
OBJECTIVE: Alterations in the hypothalamic-pituitary-thyroid axis have been reported following growth hormone (GH) replacement. The aim was to examine the relationship between changes in serum concentration of thyroid hormones and deiodinase activity in subcutaneous adipose tissue, before and after GH replacement. DESIGN: A prospective, observational study of patients receiving GH replacement as part of routine clinical care. PATIENTS: Twenty adult hypopituitary men. MEASUREMENTS: Serum TSH, thyroid hormones - free and total thyroxine (T4) and triiodothyronine (T3) and reverse T3, thyroglobulin and thyroid-binding globulin (TBG) levels were measured before and after GH substitution. Changes in serum hormone levels were compared to the activity of deiodinase isoenzymes (DIO1, DIO2 and DIO3) in subcutaneous adipose tissue. RESULTS: The mean daily dose of growth hormone (GH) was 0·34 ± 0·11 mg (range 0·15-0·5 mg). Following GH replacement, mean free T4 levels declined (-1·09 ± 1·99 pmol/l, P = 0·02). Reverse T3 levels also fell (-3·44 ± 1·42 ng/dl, P = 0·03) and free T3 levels increased significantly (+0·34 ± 0·15 pmol/l, P = 0·03). In subcutaneous fat, DIO2 enzyme activity declined; DIO1 and DIO3 activities remained unchanged following GH substitution. Serum TSH, thyroglobulin and TBG levels were unaltered by GH therapy. CONCLUSIONS: In vitro analysis of subcutaneous adipose tissue from hypopituitary human subjects demonstrates that GH replacement is associated with significant changes in deiodinase isoenzyme activity. However, the observed variation in enzyme activity does not explain the changes in the circulating concentration of thyroid hormones induced by GH replacement. It is possible that deiodinase isoenzymes are differentially regulated by GH in other tissues including liver and muscle.
Assuntos
Hormônio do Crescimento/farmacologia , Terapia de Reposição Hormonal/métodos , Hipopituitarismo/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Adulto , Idoso , Hormônio do Crescimento/administração & dosagem , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Gordura Subcutânea Abdominal/efeitos dos fármacos , Resultado do Tratamento , Adulto JovemRESUMO
Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERß influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERß agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα-/- female mice. Browning was associated with increased expression of ERß in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of ß3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERß in the SAT and very little expression of the ß3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERß in controlling browning of adipose tissue.
Assuntos
Tecido Adiposo Marrom/metabolismo , Receptor beta de Estrogênio/agonistas , Obesidade/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Fatores Etários , Animais , Benzopiranos/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Modelos Biológicos , Obesidade/genética , Fatores Sexuais , Gordura Subcutânea Abdominal/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
FGF21 improves the metabolic profile of obese animals through its actions on adipocytes. To elucidate the signaling network responsible for mediating these effects, we quantified dynamic changes in the adipocyte phosphoproteome following acute exposure to FGF21. FGF21 regulated a network of 821 phosphosites on 542 proteins. A major FGF21-regulated signaling node was mTORC1/S6K. In contrast to insulin, FGF21 activated mTORC1 via MAPK rather than through the canonical PI3K/AKT pathway. Activation of mTORC1/S6K by FGF21 was surprising because this is thought to contribute to deleterious metabolic effects such as obesity and insulin resistance. Rather, mTORC1 mediated many of the beneficial actions of FGF21 in vitro, including UCP1 and FGF21 induction, increased adiponectin secretion, and enhanced glucose uptake without any adverse effects on insulin action. This study provides a global view of FGF21 signaling and suggests that mTORC1 may act to facilitate FGF21-mediated health benefits in vivo.
Assuntos
Adipócitos/efeitos dos fármacos , Adiponectina/genética , Fatores de Crescimento de Fibroblastos/farmacologia , Complexos Multiproteicos/genética , Fosfoproteínas/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Serina-Treonina Quinases TOR/genética , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adiponectina/agonistas , Adiponectina/metabolismo , Animais , Diferenciação Celular , Desoxiglucose/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Injeções Intraperitoneais , Marcação por Isótopo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multiproteicos/agonistas , Complexos Multiproteicos/metabolismo , Fosfoproteínas/metabolismo , Proteoma/genética , Proteoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Gordura Subcutânea Abdominal/citologia , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína Desacopladora 1/agonistas , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
CONTEXT AND OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increases blood flow and triglyceride (TAG) clearance in subcutaneous (sc) abdominal adipose tissue in lean humans. The present experiments were performed to further investigate the role of insulin for the vasoactive effect of GIP in adipose tissue metabolism and whether the vasodilatory effect of GIP is dependent on C-peptide. METHODS: Six lean healthy subjects were studied. The sc abdominal adipose tissue metabolism was assessed by Fick's principle during GIP infusion (1.5 pmol/kg/min) in combination with 1) euglycemic-high insulinemic clamp (Eugluc-Hiinsu), raising plasma insulin concentrations to postprandial levels, 2) hyperglycemic-euinsulinemic clamp (Hygluc-Euinsu), and 3) hyperglycemic-hyperinsulinemic clamp, raising plasma insulin concentrations to supraphysiological levels. During the hyperglycemic clamps, endogenous insulin and C-peptide secretion were inhibited by infusion of the somatostatin analogue octreotide. RESULTS: During GIP infusion, Eugluc-Hiinsu, and hyperglycemic-hyperinsulinemic clamps, sc abdominal adipose tissue blood flow (ATBF) was similar and increased from 2.1 ± 0.2 and 2.2 ± 0.4 ml min(-1) (100 g tissue)(-1) to 7.1 ± 0.6 and 7.6 ± 0.1 ml min(-1) (100 g tissue)(-1), respectively (P < .01). ATBF remained virtually constant (2.7 ± 0.4 ml min(-1) [100 g tissue](-1)) during Hygluc-Euinsu and GIP infusion. In addition, adipose tissue TAG clearance increased significantly (P = .03), whereas free fatty acid output (P = .01), glycerol output (P = .02) and free fatty acid/glycerol release ratio (P = .04) decreased during the Eugluc-Hiinsu clamp compared to Hygluc-Euinsu clamp with GIP. CONCLUSION: In healthy lean humans, insulin is permissive for GIP to induce an increase in blood flow and TAG clearance in sc abdominal adipose tissue. This effect is independent of C-peptide.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Insulina/farmacologia , Vasoconstrição/efeitos dos fármacos , Tecido Adiposo/irrigação sanguínea , Adulto , Estudos Cross-Over , Sinergismo Farmacológico , Técnica Clamp de Glucose , Humanos , Masculino , Fluxo Sanguíneo Regional/efeitos dos fármacos , Gordura Subcutânea Abdominal/irrigação sanguínea , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/metabolismo , Vasoconstritores/farmacologia , Adulto JovemRESUMO
Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots.
Assuntos
Adipogenia , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Gordura Intra-Abdominal/metabolismo , Receptores do Ácido Retinoico/agonistas , Transdução de Sinais , Tretinoína/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/patologia , Cirurgia Bariátrica , Benzoatos/farmacologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Ontologia Genética , Humanos , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/patologia , Pessoa de Meia-Idade , Naftalenos/farmacologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , Interferência de RNA , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/metabolismo , Elementos de Resposta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Gordura Subcutânea Abdominal/citologia , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Regulação para Cima/efeitos dos fármacos , Proteínas WT1/antagonistas & inibidores , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Cetoacidose Diabética/imunologia , Lipólise , Modelos Imunológicos , Paniculite/imunologia , Transdução de Sinais , Gordura Subcutânea Abdominal/imunologia , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , Adulto , Biópsia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Cetoacidose Diabética/metabolismo , Cetoacidose Diabética/patologia , Cetoacidose Diabética/prevenção & controle , Endotoxinas/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Insulina de Ação Prolongada/administração & dosagem , Insulina de Ação Prolongada/uso terapêutico , Insulina de Ação Curta/administração & dosagem , Insulina de Ação Curta/uso terapêutico , Lipólise/efeitos dos fármacos , Masculino , Paniculite/tratamento farmacológico , Paniculite/metabolismo , Paniculite/patologia , Transdução de Sinais/efeitos dos fármacos , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Hyperglycemia represents one of possible mediators for activation of immune system and may contribute to worsening of inflammatory state associated with obesity. The aim of our study was to investigate the effect of a short-term hyperglycemia (HG) on the phenotype and relative content of immune cells in circulation and subcutaneous abdominal adipose tissue (SAAT) in obese women without metabolic complications. SUBJECTS/METHODS: Three hour HG clamp with infusion of octreotide and control investigations with infusion of octreotide or saline were performed in three groups of obese women (Group1: HG, Group 2: Octreotide, Group 3: Saline, n=10 per group). Before and at the end of the interventions, samples of SAAT and blood were obtained. The relative content of immune cells in blood and SAAT was determined by flow cytometry. Gene expression analysis of immunity-related markers in SAAT was performed by quantitative real-time PCR. RESULTS: In blood, no changes in analysed immune cell population were observed in response to HG. In SAAT, HG induced an increase in the content of CD206 negative monocytes/macrophages (p<0.05) and T lymphocytes (both T helper and T cytotoxic lymphocytes, p<0.01). Further, HG promoted an increase of mRNA levels of immune response markers (CCL2, TLR4, TNFα) and lymphocyte markers (CD3g, CD4, CD8a, TBX21, GATA3, FoxP3) in SAAT (p<0.05 and 0.01). Under both control infusions, none of these changes were observed. CONCLUSIONS: Acute HG significantly increased the content of monocytes and lymphocytes in SAAT of healthy obese women. This result suggests that the short-term HG can modulate an immune status of AT in obese subjects.
Assuntos
Saúde , Hiperglicemia/induzido quimicamente , Hiperglicemia/imunologia , Monócitos/citologia , Obesidade/complicações , Gordura Subcutânea Abdominal/imunologia , Linfócitos T/citologia , Adulto , Biomarcadores/metabolismo , Glicemia/metabolismo , Peptídeo C/sangue , Contagem de Células , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Insulina/sangue , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Octreotida/farmacologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Linfócitos T/efeitos dos fármacosRESUMO
BACKGROUND: Muscle weakness and fatigue are common symptoms in multiple sclerosis (MS). Green tea catechins such as (-)epigallocatechin-3-gallate (EGCG) are known to improve energy metabolism at rest and during exercise. OBJECTIVE: We tested the hypothesis that EGCG improves energy metabolism and substrate utilization in patients with MS. DESIGN: Eighteen patients (8 men) with relapsing-remitting MS (expanded disability status scale score <4.5, all receiving glatiramer acetate) participated in this randomized, double-blind, placebo-controlled, crossover trial at a clinical research center. All patients received EGCG (600 mg/d) and placebo over 12 wk (4-wk washout in between). After each intervention, fasting and postprandial energy expenditure (EE), as well as fat oxidation (FAOx) and carbohydrate oxidation (CHOx) rates, were measured either at rest or during 40 min of exercise (0.5 W/kg). At rest, blood samples and microdialysates from adipose tissue and skeletal muscle were also taken. RESULTS: At rest, postprandial EE and CHOx, as well as adipose tissue perfusion and glucose supply, were significantly lower in men but higher in women receiving EGCG compared with placebo. During exercise, postprandial EE was lower after EGCG than after placebo, indicating an increased working efficiency (men > women). After placebo, exercise EE was mainly fueled by FAOx in both men and women. After EGCG, there was a shift to a higher and more stable CHOx during exercise in men but not in women. CONCLUSIONS: Our data indicate that EGCG given to patients with MS over 12 wk improves muscle metabolism during moderate exercise to a greater extent in men than in women, possibly because of sex-specific effects on autonomic and endocrine control.
Assuntos
Catequina/análogos & derivados , Suplementos Nutricionais , Metabolismo Energético , Esclerose Múltipla Recidivante-Remitente/dietoterapia , Músculo Esquelético/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Gordura Subcutânea Abdominal/metabolismo , Adulto , Metabolismo dos Carboidratos/efeitos dos fármacos , Catequina/efeitos adversos , Catequina/uso terapêutico , Terapia Combinada/efeitos adversos , Estudos Cross-Over , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Feminino , Acetato de Glatiramer , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Atividade Motora , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Período Pós-Prandial , Índice de Gravidade de Doença , Caracteres Sexuais , Gordura Subcutânea Abdominal/efeitos dos fármacosRESUMO
Of 37 subjects aged 25-91 y (mean 67 y), mineral oil hydrocarbons were measured in subcutaneous abdominal fat tissue, mesenteric lymph nodes (MLN), spleen, liver and lung, for some of them also in kidney, heart and brain. No mineral oil aromatic hydrocarbons (MOAH) were detected. The mean concentration of mineral oil saturated hydrocarbons (MOSH) in the mesenteric lymph nodes was 223 mg/kg, in liver 131 mg/kg, in fat tissue 130 mg/kg, in spleen 93 mg/kg and in lung 12 mg/kg. They were clearly lower in kidney, heart and brain. The maxima, found in MLN and spleen, were 1390 and 1400 mg/kg, respectively. For a quarter of the subjects a total amount of MOSH in the body above 5 g was calculated. The MOSH composition in the fat tissue and the MLN appeared virtually identical and varied little between the subjects. It was centered on the n-alkanes C23-C24, ranged from C16 to C35 and included hydrocarbons of plant origin. The MOSH in spleen and liver had almost the same composition for a given subject, but varied somewhat between subjects. They were centered between C25 and C27, ranged from C18 to beyond C45 and were without hydrocarbons of plant origin. Part of the MOSH seem to be strongly accumulated, resulting in far higher concentrations in human tissues related to exposure than observed in shorter term animal experiments. The composition of the accumulated MOSH does not support that Class I mineral oils, sometimes termed "food grade", are less accumulated in the human body than Class II and III oils, which questions the present classification.
Assuntos
Hidrocarbonetos Aromáticos/metabolismo , Óleo Mineral/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Baço/efeitos dos fármacos , Baço/metabolismo , Gordura Subcutânea Abdominal/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to determine whether cyclooxygenase inhibition improves vascular dysfunction of adipose microvessels from obese humans. DESIGN AND METHODS: In 20 obese subjects (age 37 ± 12 years, BMI 47 ± 8 kg/m²), subcutaneous and visceral fat were collected during bariatric surgery and characterized for adipose depot-specific gene expression, endothelial cell phenotype, and microvascular function. Vasomotor function was assessed in response to endothelium-dependent agonists using videomicroscopy of small arterioles from fat. RESULTS: Arterioles from visceral fat exhibited impaired endothelium-dependent, acetylcholine-mediated vasodilation, compared to the subcutaneous depot (P < 0.001). Expression of mRNA transcripts relevant to the cyclooxygenase pathway was upregulated in visceral compared to subcutaneous fat. Pharmacological inhibition of cyclooxygenase with indomethacin improved endothelium-dependent vasodilator function of arterioles from visceral fat by twofold (P = 0.01), whereas indomethacin had no effect in the subcutaneous depot. Indomethacin increased activation via serine-1177 phosphorylation of endothelial nitric oxide synthase in response to acetylcholine in endothelial cells from visceral fat. Inhibition of endothelial nitric oxide synthase with N(ω)-nitro-L-arginine methyl ester abrogated the effects of cyclooxygenase-inhibition suggesting that vascular actions of indomethacin were related to increased nitric oxide bioavailability. CONCLUSIONS: Our findings suggest that cyclooxygenase-mediated vasoconstrictor prostanoids partly contribute to endothelial dysfunction of visceral adipose arterioles in human obesity.