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1.
J Lipid Res ; 64(2): 100324, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36586437

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA-approved treatments, but FXR agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that high-fat diet-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo
2.
Can J Econ ; 55(Suppl 1): 406-445, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38607897

RESUMO

We develop a methodology to track and quantify the economic impacts of lockdown and reopening policies by Canadian provinces in response to the COVID-19 pandemic, using data that is available with a relatively short time lag. To do so, we adapt, calibrate and implement a dynamic, seasonally adjusted, input-output model with supply constraints. Our framework allows us to quantify potential scenarios that allow for dynamic complementarities between industries, seasonal fluctuations and changes in demand composition. Taking account of the observed variation in reopening strategies across provinces, we estimate the costs of the policy response in terms of lost hours of employment and production. Among other results, we show how a more aggressive response, even though it imposes higher economic costs in the short run, can lead to lower economic costs in the long run if it means avoiding future waves of lockdowns.


Quantification des impacts économiques des politiques associées à la COVID­19dans les provinces canadiennes en temps réel (ou presque). On développe une méthodologie pour identifier et quantifier les impacts économiques des mesures de confinement et des politiques de déconfinement dans chacune des provinces canadiennes en réponse à la pandémie de la COVID­19 en utilisant des données publiées avec un court décalage. Pour ce faire, on adapte, calibre et implémente un modèle d'entrées­sorties dynamique désaisonnalisé avec des contraintes au niveau de l'offre. Notre modèle nous permet de quantifier des scénarios potentiels qui incorporent les complémentarités dynamiques entre les industries, les fluctuations saisonnières et les changements dans la composition de la demande. En prenant en compte les variations observées dans les stratégies de déconfinement de chaque province, on estime les coûts des politiques en ce qui a trait aux pertes d'heures travaillées et de production. Parmi les autres résultats observés, on démontre qu'une réponse plus agressive, quoique plus coûteuse à court terme, peut mener à des coûts économiques moins élevés à long­terme si elle permet d'éviter des vagues de reconfinement.

3.
Nat Commun ; 11(1): 3360, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620763

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate ß-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.


Assuntos
Ácidos Graxos/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Fígado/patologia , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Idoso , Animais , Conjuntos de Dados como Assunto , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP40/antagonistas & inibidores , Proteínas de Choque Térmico HSP40/genética , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Chaperonas Moleculares/antagonistas & inibidores , Chaperonas Moleculares/genética , Nanopartículas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução/efeitos dos fármacos , Cultura Primária de Células , RNA Interferente Pequeno/administração & dosagem , RNA-Seq
4.
Endocrinology ; 148(2): 501-6, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17095592

RESUMO

It has been recently proposed that obestatin, a peptide encoded by the ghrelin gene, reduces food intake by activating the orphan G protein-coupled receptor GPR39. To gain further insights into the role of GPR39 in body weight homeostasis, we characterized the phenotype of mice with targeted disruption of the GPR39 gene. Body weight, adiposity, and food intake were found to be similar between GPR39(+/+) and GPR39(-/-) mice. Furthermore, fasting glucose and insulin levels were similar between both genotypes. Injection of obestatin peptide (1 micromol/kg, ip) obtained from multiple sources did not consistently inhibit food intake in wild-type mice after an overnight fast, and no difference in food intake was observed between wild-type and GPR39 knockout mice after injection of the peptide. Finally, ectopic expression of GPR39 in HEK293T cells revealed a constitutive activation of the receptor that was unaffected by stimulation with obestatin. Our phenotypic characterization suggests that GPR39 is not a major modulator of food intake in mice, although a more subtle role cannot be excluded. The role of GPR39 in normal physiology requires further study and should be conducted independently of the function of obestatin.


Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Homeostase/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Grelina , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hormônios Peptídicos/genética , Hormônios Peptídicos/metabolismo , Hormônios Peptídicos/farmacologia , Fenótipo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/metabolismo , Transfecção
5.
Endocrinology ; 158(8): 2556-2571, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28475811

RESUMO

Growth hormone (GH) and insulinlike growth factor 1 (IGF-1) are anabolic hormones that facilitate somatic and skeletal growth and regulate metabolism via endocrine and autocrine/paracrine mechanisms. We hypothesized that excess tissue production of GH would protect skeletal growth and integrity in states of reduction in serum IGF-1 levels. To test our hypothesis, we used bovine GH (bGH) transgenic mice as a model of GH hypersecretion and ablated the liver-derived acid-labile subunit, which stabilizes IGF-1 complexes with IGF-binding protein-3 and -5 in circulation. We used a genetic approach to create bGH/als gene knockout (ALSKO) mice and small interfering RNA (siRNA) gene-silencing approach to reduce als or igf-1 gene expression. We found that in both models, decreased IGF-1 levels in serum were associated with decreased body and skeletal size of the bGH mice. Excess GH produced more robust bones but compromised mechanical properties in male mice. Excess GH production in tissues did not protect from trabecular bone loss in response to reductions in serum IGF-1 (in bGH/ALSKO or bGH mice treated with siRNAs). Reduced serum IGF-1 levels in the bGH mice did not alleviate the hyperinsulinemia and did not resolve liver or kidney pathologies that resulted from GH hypersecretion. We concluded that reduced serum IGF-1 levels decrease somatic and skeletal growth even in states of excess GH.


Assuntos
Hormônio do Crescimento/metabolismo , Fígado/metabolismo , Animais , Desenvolvimento Ósseo/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Bovinos , Feminino , Regulação da Expressão Gênica/fisiologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Hormônio do Crescimento/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoclastos/fisiologia , Subunidades Proteicas , RNA Interferente Pequeno , Distribuição Aleatória
6.
Diabetes ; 54(9): 2674-84, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16123357

RESUMO

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid approximately 6 vs. approximately 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by approximately 70% during saline infusion (EGP(150-180 min) 11 +/- 1 vs. 3 +/- 1 mumol . kg(-1) . min(-1), P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (R(d)) was approximately 33% lower during amino acid infusion (R(d) (330-360 min) 50 +/- 4 vs. 75 +/- 6 mumol . kg(-1) . min(-1), P = 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation. In conclusion, amino acids impair 1) insulin-mediated suppression of glucose production and 2) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid-infused humans.


Assuntos
Aminoácidos/metabolismo , Glucose/metabolismo , Resistência à Insulina/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Células Cultivadas , Ativação Enzimática/fisiologia , Humanos , Masculino , Músculo Esquelético/citologia , Fosforilação
7.
Endocrinology ; 146(3): 1328-37, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15576463

RESUMO

The mammalian target of rapamycin (mTOR) pathway has recently emerged as a chronic modulator of insulin-mediated glucose metabolism. In this study, we evaluated the involvement of this pathway in the acute regulation of insulin action in both 3T3-L1 and human adipocytes. Insulin rapidly (t(1/2) = 5 min) stimulated the mTOR pathway, as reflected by a 10-fold stimulation of 70-kDa ribosomal S6 kinase 1 (S6K1) activity in 3T3-L1 adipocytes. Inhibition of mTOR/S6K1 by rapamycin increased insulin-stimulated glucose transport by as much as 45% in 3T3-L1 adipocytes. Activation of mTOR/S6K1 by insulin was associated with a rapamycin-sensitive increase in Ser636/639 phosphorylation of insulin receptor substrate (IRS)-1 but, surprisingly, did not result in impaired IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. However, insulin-induced activation of Akt was increased by rapamycin. Insulin also activated S6K1 and increased phosphorylation of IRS-1 on Ser636/639 in human adipocytes. As in murine cells, rapamycin treatment of human adipocytes inhibited S6K1, blunted Ser636/639 phosphorylation of IRS-1, leading to increased Akt activation and glucose uptake by insulin. Further studies in 3T3-L1 adipocytes revealed that rapamycin prevented the relocalization of IRS-1 from the low-density membranes to the cytosol in response to insulin. Furthermore, inhibition of mTOR markedly potentiated the ability of insulin to increase PI 3,4,5-triphosphate levels concomitantly with an increased phosphorylation of Akt at the plasma membrane, low-density membranes, and cytosol. However, neither GLUT4 nor GLUT1 translocation induced by insulin were increased by rapamycin treatment. Taken together, these results indicate that the mTOR pathway is an important modulator of the signals involved in the acute regulation of insulin-stimulated glucose transport in 3T3-L1 and human adipocytes.


Assuntos
Células 3T3-L1/metabolismo , Adipócitos/citologia , Glucose/metabolismo , Insulina/metabolismo , Proteínas Quinases/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , 3-O-Metilglucose/metabolismo , Adipócitos/metabolismo , Animais , Diferenciação Celular , Membrana Celular/metabolismo , Desoxiglucose/metabolismo , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 4 , Humanos , Immunoblotting , Imunoprecipitação , Proteínas Substratos do Receptor de Insulina , Cinética , Camundongos , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina/química , Transdução de Sinais , Sirolimo/farmacologia , Frações Subcelulares , Serina-Treonina Quinases TOR , Fatores de Tempo
8.
Diabetes ; 52(1): 29-37, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12502490

RESUMO

Diet-induced obesity is known to cause peripheral insulin resistance in rodents. We have recently found that feeding cod protein to high-fat-fed rats prevents the development of insulin resistance in skeletal muscle. In the present study, we have further explored the cellular mechanisms behind this beneficial effect of cod protein on skeletal muscle insulin sensitivity. Rats were fed a standard chow diet or a high-fat diet in which the protein source was either casein, soy, or cod proteins for 4 weeks. Whole-body and muscle glucose disposal were reduced by approximately 50% in rats fed high-fat diets with casein or soy proteins, but these impairments were not observed in animals fed cod protein. Insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS) proteins were similar in muscle of chow- and high-fat-fed rats regardless of the dietary protein source. However, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was severely impaired (-60%) in muscle of high-fat-fed rats consuming casein or soy protein. In marked contrast, feeding rats with cod protein completely prevented the deleterious effect of fat feeding on insulin-stimulated PI 3-kinase activity. The activation of the downstream kinase Akt/PKB by insulin, assessed by in vitro kinase assay and phosphorylation of GSK-3beta, were also impaired in muscle of high-fat-fed rats consuming casein or soy protein, but these defects were also fully prevented by dietary cod protein. However, no effect of cod protein was observed on atypical protein kinase C activity. Normalization of PI 3-kinase/Akt activation by insulin in rats fed high-fat diets with cod protein was associated with improved translocation of GLUT4 to the T-tubules but not to the plasma membrane. Taken together, these results show that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance by normalizing insulin activation of the PI 3-kinase/Akt pathway and by selectively improving GLUT4 translocation to the T-tubules.


Assuntos
Proteínas Alimentares/farmacologia , Produtos Pesqueiros , Insulina/metabolismo , Proteínas Musculares , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases , Animais , Transporte Biológico , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Ativação Enzimática , Transportador de Glucose Tipo 4 , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Masculino , Proteínas de Transporte de Monossacarídeos/metabolismo , Músculo Esquelético/metabolismo , Obesidade/etiologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Tirosina/metabolismo
9.
Front Biosci ; 8: d1072-84, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12957810

RESUMO

Glucose transport across the cell surface is a key regulatory step for glucose metabolism in skeletal muscle. Both insulin and exercise increase glucose transport into myofibers through glucose transporter (GLUT) proteins. Skeletal muscle expresses several members of the GLUT family but the GLUT4 glucose transporter is considered the main "regulatable" isoform that is modulated by insulin and contraction. Glucose transport rate can be stimulated either by recruitment of GLUT4 units from intracellular storage vesicles or through activation of cell surface transporters. Insulin activates GLUT4 translocation through a complex signaling cascade involving both the lipid kinase phosphatidylinositol 3-kinase and the proto-oncoprotein c-Cbl. Contraction, on the other hand, appears to trigger GLUT4 translocation at least in part through activation of the metabolite-sensing 5'-AMP-activated protein kinase. Furthermore, recent studies suggest that p38 MAP kinase activation represents a point of convergence of the signaling pathways utilized by insulin and contraction to increase GLUT4 activation at the cell surface. This review will summarize our current knowledge of these alternative pathways of GLUT4 regulation in skeletal muscle.


Assuntos
Insulina/fisiologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Contração Muscular/fisiologia , Proteínas Musculares , Músculo Esquelético/fisiologia , Animais , Transportador de Glucose Tipo 4 , Humanos , Proteínas de Transporte de Monossacarídeos/fisiologia , Músculo Esquelético/química , Transporte Proteico/fisiologia , Transdução de Sinais/fisiologia
10.
PLoS One ; 9(3): e92608, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24658703

RESUMO

Brown adipose tissue (BAT) plays a pivotal role in promoting energy expenditure by the virtue of uncoupling protein-1 (UCP-1) that differentiates BAT from its energy storing white adipose tissue (WAT) counterpart. The clinical implication of "classical" BAT (originates from Myf5 positive myoblastic lineage) or the "beige" fat (originates through trans-differentiation of WAT) activation in improving metabolic parameters is now becoming apparent. However, the inducers and endogenous molecular determinants that govern the lineage commitment and differentiation of classical BAT remain obscure. We report here that in the absence of any forced gene expression, stimulation with bone morphogenetic protein 6 (BMP6) induces brown fat differentiation from skeletal muscle precursor cells of murine and human origins. Through a comprehensive transcriptional profiling approach, we have discovered that two days of BMP6 stimulation in C2C12 myoblast cells is sufficient to induce genes characteristic of brown preadipocytes. This developmental switch is modulated in part by newly identified regulators, Optineurin (Optn) and Cyclooxygenase-2 (Cox2). Furthermore, pathway analyses using the Causal Reasoning Engine (CRE) identified additional potential causal drivers of this BMP6 induced commitment switch. Subsequent analyses to decipher key pathway that facilitates terminal differentiation of these BMP6 primed cells identified a key role for Insulin Like Growth Factor-1 Receptor (IGF-1R). Collectively these data highlight a therapeutically innovative role for BMP6 by providing a means to enhance the amount of myogenic lineage derived brown fat.


Assuntos
Tecido Adiposo Marrom/metabolismo , Proteína Morfogenética Óssea 6/metabolismo , Mioblastos/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Animais , Proteína Morfogenética Óssea 6/genética , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Linhagem Celular , Análise por Conglomerados , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Proteínas de Membrana Transportadoras , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Oxirredução , Fenótipo , Receptor IGF Tipo 1 , Transdução de Sinais , Fator de Transcrição TFIIIA/genética , Fator de Transcrição TFIIIA/metabolismo , Proteína Desacopladora 1
11.
Endocrinology ; 153(9): 4290-303, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22753645

RESUMO

Coiled-coil domain containing 80 (Ccdc80) is a secreted protein highly enriched in mouse and human white adipose tissue (WAT) that plays an important role during adipocyte differentiation in vitro. To investigate the physiological function of Ccdc80 in energy and glucose homeostasis, we generated mice in which the gene encoding Ccdc80 was disrupted. Mice lacking Ccdc80 showed increased sensitivity to diet-induced hyperglycemia and glucose intolerance while displaying reduced glucose-stimulated insulin secretion in vivo. Gene expression analysis by microarray revealed that only 10 transcripts were simultaneously altered in pancreas, skeletal muscle, and WAT from Ccdc80(-/-) mice, including some components of the circadian clock. Expression of the core clock member Arntl/Bmal1 was reduced whereas that of the oscillating transcription factors Dbp and Tef was increased in all tissues examined. Furthermore, knockdown of Ccdc80 in 3T3-L1 cells led to an increase of Dbp mRNA levels during adipocyte differentiation, suggesting that Ccdc80 might be involved in the regulation of this gene in a cell-autonomous manner. Importantly, transcriptional alterations in Ccdc80(-/-) mice were associated with changes in feeding behavior, increased caloric intake, decreased energy expenditure, and obesity. Taken together, our results suggest that Ccdc80 is a novel modulator of glucose and energy homeostasis during diet-induced obesity.


Assuntos
Glucose/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Obesidade/metabolismo , Células 3T3-L1 , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas da Matriz Extracelular , Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Obesos , Músculo Esquelético/metabolismo , Obesidade/genética , Pâncreas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
J Biol Chem ; 284(12): 8136-47, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19141617

RESUMO

Adipocyte-secreted proteins play important roles in metabolic regulation through autocrine, paracrine, and endocrine mechanisms. Using transcriptional profiling, we identified coiled-coil domain containing 80 (Ccdc80; also known as DRO1 and URB) as a novel secreted protein highly expressed in white adipose tissue. In 3T3-L1 cells Ccdc80 is expressed and secreted in a biphasic manner with high levels in postconfluent preadipocytes and terminally differentiated adipocytes. To determine whether Ccdc80 regulates adipocyte differentiation, Ccdc80 expression was manipulated using both knockdown and overexpression approaches. Small hairpin RNA-mediated silencing of Ccdc80 in 3T3-L1 cells inhibits adipocyte differentiation. This phenotype was partially reversed by treating the knockdown cells with Ccdc80-containing conditioned medium from differentiated 3T3-L1 cells. Molecular studies indicate that Ccdc80 is required for the full inhibition of T-cell factor-mediated transcriptional activity, down-regulation of Wnt/beta-catenin target genes during clonal expansion, and the subsequent induction of C/EBPalpha and peroxisome proliferator-activated receptor gamma. Surprisingly, overexpression of Ccdc80 in 3T3-L1 cells also inhibits adipocyte differentiation without affecting the repression of the Wnt/beta-catenin signaling pathway. Taken together, these data suggest that Ccdc80 plays dual roles in adipogenesis by mechanisms that involve at least in part down-regulation of Wnt/beta-catenin signaling and induction of C/EBPalpha and peroxisome proliferator-activated receptor gamma.


Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Tecido Adiposo/metabolismo , Glicoproteínas/metabolismo , Transdução de Sinais/fisiologia , Células 3T3-L1 , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/fisiologia , Proteínas da Matriz Extracelular , Inativação Gênica , Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
13.
Endocrinology ; 150(6): 2586-95, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19213841

RESUMO

GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes.


Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Envelhecimento/metabolismo , Animais , Células Cultivadas , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Inativação Gênica/fisiologia , Glucose/metabolismo , Glucose/farmacologia , Proteínas de Homeodomínio/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Interferência de RNA/fisiologia , Transativadores/metabolismo
14.
Annu Rev Nutr ; 27: 293-310, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17666010

RESUMO

Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. Varying the quality rather than the quantity of proteins has been shown to modulate insulin resistance induced by Western diets and has revealed that proteins derived from fish might have the most desirable effects on insulin sensitivity. In vitro and in vivo data also support an important role of amino acids in glucose homeostasis through modulation of insulin action on muscle glucose transport and hepatic glucose production, secretion of insulin and glucagon, as well as gene and protein expression in various tissues. Moreover, amino acid signaling is integrated by mammalian target of rapamycin, a nutrient sensor that operates a negative feedback loop toward insulin receptor substrate 1 signaling, promoting insulin resistance for glucose metabolism. This integration suggests that modulating dietary proteins and the flux of circulating amino acids generated by their consumption and digestion might underlie powerful new approaches to treat various metabolic diseases such as obesity and diabetes.


Assuntos
Aminoácidos/fisiologia , Glicemia/metabolismo , Proteínas Alimentares/administração & dosagem , Gluconeogênese/efeitos dos fármacos , Resistência à Insulina , Aminoácidos/metabolismo , Proteínas Alimentares/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Gluconeogênese/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Saciação/efeitos dos fármacos , Saciação/fisiologia
15.
Proc Natl Acad Sci U S A ; 104(35): 14056-61, 2007 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-17709744

RESUMO

S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS-1 phosphorylation in a physiological setting of nutrient overload is unresolved. Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C-terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation. Consistent with this finding, phosphorylation of IRS-1 Ser-1101 is increased in the liver of obese db/db and wild-type, but not S6K1(-/-), mice maintained on a high-fat diet and is blocked by siRNA knockdown of S6K1 protein. Finally, infusion of amino acids in humans leads to the concomitant activation of S6K1, phosphorylation of IRS-1 Ser-1101, a reduction in IRS-1 function, and insulin resistance in skeletal muscle. These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation.


Assuntos
Resistência à Insulina/fisiologia , Obesidade/fisiopatologia , Fosfoproteínas/metabolismo , Animais , Humanos , Proteínas Substratos do Receptor de Insulina , Camundongos , Estado Nutricional , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/fisiologia , Fosforilação , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Serina , Sirolimo/farmacologia
16.
Curr Opin Clin Nutr Metab Care ; 8(4): 457-62, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15930974

RESUMO

PURPOSE OF REVIEW: An increasing number of studies point towards an important role of dietary proteins and amino acids in the modulation of insulin action in peripheral tissues. The purpose of this review is to discuss how these nutrients affect insulin sensitivity and the potential mechanism by which they exert their action. RECENT FINDINGS: Increased plasma amino acid availability in both animals and humans has been shown to cause enhanced translation initiation and protein synthesis and the inhibition of insulin-stimulated glucose transport in skeletal muscle. Moreover, dietary interventions in animals fed proteins from various sources resulted in drastically different outcomes in terms of glucose metabolism and insulin signaling in skeletal muscles. Finally, amino acids, particularly leucine, were shown to modulate insulin action by specifically activating the mammalian target of rapamycin nutrient sensing pathway. SUMMARY: Dietary proteins and amino acids are important modulators of glucose metabolism and insulin signaling via their ability, at least partly, to modulate the mammalian target of rapamycin pathway.


Assuntos
Aminoácidos/farmacologia , Proteínas Alimentares/farmacologia , Insulina/metabolismo , Sirolimo/farmacologia , Aminoácidos/administração & dosagem , Animais , Proteínas Alimentares/administração & dosagem , Biossíntese de Proteínas , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR
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