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1.
Adipocyte ; 11(1): 69-83, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35094654

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that interacts via 5 G-protein coupled receptors, S1PR1-5, to regulate signalling pathways critical to biological processes including cell growth, immune cell trafficking, and inflammation.We demonstrate that in Type 2 diabetic (T2D) subjects, plasma S1P levels significantly increased in response to the anti-diabetic drug, rosiglitazone, and, S1P levels correlated positively with measures of improved glucose homeostasis. In HFD-induced obese C57BL/6 J mice S1PR3 gene expression was increased in adipose tissues (AT) and liver compared with low fat diet (LFD)-fed counterparts. On a HFD, weight gain was similar in both S1PR3-/- mice and WT littermates; however, HFD-fed S1PR3-/- mice exhibited a phenotype of partial lipodystrophy, exacerbated insulin resistance and glucose intolerance. This worsened metabolic phenotype of HFD-fed S1PR3-/- mice was mechanistically linked with increased adipose inflammation, adipose macrophage and T-cell accumulation, hepatic inflammation and hepatic steatosis. In 3T3-L1 preadipocytes S1P increased adipogenesis and S1P-S1PR3 signalling regulated the expression of PPARγ, suggesting a novel role for this signalling pathway in the adipogenic program. These results reveal an anti-diabetic role for S1P, and, that S1P-S1PR3 signalling in the adipose and liver defends against excessive inflammation and steatosis to maintain metabolic homeostasis at key regulatory pathways.


Assuntos
Fenômenos Biológicos , Fígado Gorduroso , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Inflamação/metabolismo , Lisofosfolipídeos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade , Esfingosina/análogos & derivados , Receptores de Esfingosina-1-Fosfato
2.
Am J Physiol Endocrinol Metab ; 306(7): E756-68, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24473437

RESUMO

Adipose dysfunction resulting from chronic inflammation and impaired adipogenesis has increasingly been recognized as a major contributor to obesity-mediated insulin resistance, but the molecular mechanisms that maintain healthy adipocytes and limit adipose inflammation remain unclear. Here, we used genetic and pharmacological approaches to delineate a novel role for sphingosine kinase 1 (SK1) in metabolic disorders associated with obesity. SK1 phosphorylates sphingosine to form sphingosine 1 phosphate (S1P), a bioactive sphingolipid with numerous roles in inflammation. SK1 mRNA expression was increased in adipose tissue of diet-induced obese (DIO) mice and obese type 2 diabetic humans. In DIO mice, SK1 deficiency increased markers of adipogenesis and adipose gene expression of the anti-inflammatory molecules IL-10 and adiponectin and reduced adipose tissue macrophage (ATM) recruitment and proinflammatory molecules TNFα and IL-6. These changes were associated with enhanced insulin signaling in adipose and muscle and improved systemic insulin sensitivity and glucose tolerance in SK1(-/-) mice. Specific pharmacological inhibition of SK1 in WT DIO mice also reduced adipocyte and ATM inflammation and improved overall glucose homeostasis. These data suggest that the SK1-S1P axis could be an attractive target for the development of treatments to ameliorate adipose inflammation and insulin resistance associated with obesity and type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Mediadores da Inflamação/metabolismo , Resistência à Insulina/genética , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Adipócitos/imunologia , Adipócitos/metabolismo , Tecido Adiposo/imunologia , Adulto , Idoso , Animais , Estudos de Casos e Controles , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Paniculite/complicações , Paniculite/genética , Paniculite/metabolismo
3.
Nat Med ; 17(11): 1490-7, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22019885

RESUMO

Tissue factor, the initiator of the coagulation cascade, mediates coagulation factor VIIa-dependent activation of protease-activated receptor 2 (PAR2). Here we delineate a role for this signaling pathway in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of tissue factor were protected from weight gain and insulin resistance induced by a high-fat diet. In hematopoietic cells, genetic ablation of tissue factor-PAR2 signaling reduced adipose tissue macrophage inflammation, and specific pharmacological inhibition of macrophage tissue factor signaling rapidly ameliorated insulin resistance. In contrast, nonhematopoietic cell tissue factor-VIIa-PAR2 signaling specifically promoted obesity. Mechanistically, adipocyte tissue factor cytoplasmic domain-dependent VIIa signaling suppressed Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte tissue factor in vivo reversed these effects of tissue factor-VIIa signaling and rapidly increased energy expenditure. Thus, inhibition of tissue factor signaling is a potential therapeutic avenue for improving impaired metabolism and insulin resistance in obesity.


Assuntos
Tecido Adiposo/patologia , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Obesidade/etiologia , Receptor PAR-2/metabolismo , Transdução de Sinais/fisiologia , Tromboplastina/metabolismo , Tecido Adiposo/metabolismo , Animais , Transplante de Medula Óssea , Fator VIIa/metabolismo , Glucose/metabolismo , Inflamação/patologia , Resistência à Insulina , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Receptor PAR-2/genética , Tromboplastina/genética , Quimeras de Transplante
4.
Adv Exp Med Biol ; 721: 67-86, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21910083

RESUMO

Although obesity is a complex metabolic disorder often associated with insulin resistance, hyperinsulinemia and Type 2 diabetes, as well as with accelerated atherosclerosis, the molecular changes in obesity that promote these disorders are not completely understood. Several mechanisms have been proposed to explain how increased adipose tissue mass affects whole body insulin resistance and cardiovascular risk. One theory is that increased adipose derived inflammatory cytokines induces a chronic inflammatory state that not only increases cardiovascular risk, but also antagonizes insulin signaling and mitochondrial function and thereby impair glucose hemostasis. Another suggests that lipid accumulation in nonadipose tissues not suited for fat storage leads to the buildup of bioactive lipids that inhibit insulin signaling and metabolism. Recent evidence demonstrates that sphingolipid metabolism is dysregulated in obesity and specific sphingolipids may provide a common pathway that link excess nutrients and inflammation to increased metabolic and cardiovascular risk. This chapter will focus primarily on the expression and regulation of adipose and plasma ceramide biosynthesis in obesity and, its potential contribution to the pathogenesis of obesity and the metabolic syndrome.


Assuntos
Tecido Adiposo/metabolismo , Ceramidas/biossíntese , Obesidade/metabolismo , Adipocinas/fisiologia , Animais , Peso Corporal/fisiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Citocinas/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacocinética , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Humanos , Inflamação/metabolismo , Resistência à Insulina , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica , Obesidade/etiologia , Estresse Oxidativo , Esfingolipídeos/metabolismo
5.
J Biol Chem ; 284(31): 20692-8, 2009 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-19494115

RESUMO

Obese adipose tissue (AT) is associated with chronic inflammation, and we hypothesized that the keratinocyte-derived chemokine (KC), the mouse ortholog of human interleukin-8, plays a role in obesity-mediated AT inflammation and the subsequent manifestation of insulin resistance. KC expression is increased in the AT and plasma of genetically (ob/ob) and high fat diet-induced obese mouse models, and this increase may be mediated by the elevated leptin and tumor necrosis factor-alpha levels associated with obesity. Obesity-induced KC expression occurs primarily in stromal vascular cells and not in adipocytes, and it is high in preadipocytes and decreases during adipogenesis. Although KC has no effect on adipogenesis, it induces adipocyte expression of inflammatory factors and the insulin resistance mediator, suppressor of cytokine signaling 3. Using chimeric mice deficient in the KC receptor CXCR2 in their bone marrow, we show that the lack of CXCR2 in hematopoietic cells is sufficient to protect from adipose and skeletal muscle macrophage recruitment and development of insulin resistance in diet-induced obese mice. These studies suggest that KC and its receptor CXCR2 are potential targets for the development of new therapeutic approaches for treatment of obesity-related insulin resistance, type II diabetes, and related cardiovascular diseases.


Assuntos
Tecido Adiposo/metabolismo , Movimento Celular , Quimiocinas/metabolismo , Glucose/metabolismo , Homeostase , Macrófagos/patologia , Obesidade/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Movimento Celular/efeitos dos fármacos , Dieta , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Leptina/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/patologia , Receptores de Interleucina-8B/deficiência , Fator de Necrose Tumoral alfa/farmacologia
6.
Am J Physiol Endocrinol Metab ; 297(1): E211-24, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19435851

RESUMO

Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-alpha (TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.


Assuntos
Peso Corporal/fisiologia , Ceramidas/biossíntese , Metabolismo Energético/fisiologia , Síndrome Metabólica/metabolismo , Tecido Adiposo/patologia , Animais , Ceramidas/sangue , Ceramidas/fisiologia , Ácidos Graxos Monoinsaturados/farmacologia , Canais Iônicos/metabolismo , Lisofosfolipídeos/sangue , Masculino , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/fisiologia , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/sangue , Esfingosina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteína Desacopladora 3
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