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1.
Mol Metab ; 24: 139-148, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003943

RESUMO

OBJECTIVE: The susceptibility to abdominal obesity and the metabolic syndrome is determined to a substantial extent during childhood and adolescence, when key adipose tissue characteristics are established. Although the general impact of postnatal nutrition is well known, it is not clear how specific dietary components drive adipose tissue growth and how this relates to the risk of metabolic dysfunction in adulthood. METHODS: Adipose tissue growth including cell proliferation was analyzed in juvenile mice upon dietary manipulation with in vivo nucleotide labeling. The proliferative response of progenitors to specific fatty acids was assayed in primary cultures. Long-term metabolic consequences were assessed through transient dietary manipulation post-weaning with a second obesogenic challenge in adulthood. RESULTS: Dietary lipids stimulated adipose tissue progenitor cell proliferation in juvenile mice independently of excess caloric intake and calorie-dependent adipocyte hypertrophy. Excess calories increased mitogenic IGF-1 levels systemically, whereas palmitoleic acid was able to enhance the sensitivity of progenitors to IGF-1, resulting in synergistic stimulation of proliferation. Early transient consumption of excess lipids promoted hyperplastic adipose tissue expansion in response to a second dietary challenge in adulthood and this correlated with abdominal obesity and hyperinsulinemia. CONCLUSIONS: Dietary lipids and calories differentially and synergistically drive adipose tissue proliferative growth and the programming of the metabolic syndrome in childhood.

2.
Nat Med ; 25(4): 641-655, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936549

RESUMO

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.


Assuntos
Plaquetas/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Transgênicos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Contagem de Plaquetas
3.
EMBO Mol Med ; 10(8)2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29973382

RESUMO

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.

4.
J Nutr Biochem ; 57: 189-196, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29751292

RESUMO

Recent studies have demonstrated that dietary protein dilution (PD) can promote metabolic inefficiency and improve glucose metabolism. However, whether PD can promote other aspects of metabolic health, such as improve systemic lipid metabolism, and mechanisms therein remains unknown. Mouse models of obesity, such as high-fat-diet-fed C57Bl/6 N mice, and New Zealand Obese mice were fed normal (i.e., 20%P) and protein-dilute (i.e., 5%EP) diets. FGF21-/- and Cd36-/- and corresponding littermate +/+ controls were also studied to examine gene-diet interactions. Here, we show that chronic PD retards the development of hypertrigylceridemia and fatty liver in obesity and that this relies on the induction of the hepatokine fibroblast growth factor 21 (FGF21). Furthermore, PD greatly enhances systemic lipid homeostasis, the mechanisms by which include FGF21-stimulated, and cluster of differentiation 36 (CD36) mediated, fatty acid clearance by oxidative tissues, such as heart and brown adipose tissue. Taken together, our preclinical studies demonstrate a novel nutritional strategy, as well as highlight a role for FGF21-stimulated systemic lipid metabolism, in combating obesity-related dyslipidemia.

5.
Sci Signal ; 11(527)2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29692363

RESUMO

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as ß3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFß signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFß signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by ß3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

6.
EMBO J ; 36(14): 1999-2017, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28623240

RESUMO

Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole-body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity-related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies.


Assuntos
Tecido Adiposo/patologia , Metabolismo Energético , Metabolismo dos Lipídeos , Adipocinas , Animais , Atrofia/patologia , Atrofia/fisiopatologia , Homeostase , Humanos , Obesidade/patologia , Obesidade/fisiopatologia
7.
Methods Mol Biol ; 1566: 37-48, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28244039

RESUMO

Appropriate cell models are necessary for the investigation of thermogenic beige adipocyte differentiation from progenitor cells. Here, we describe a primary cell culture method that is based on defined progenitor cells from murine white adipose tissue and aims at minimizing confounding factors including cell heterogeneity and nonphysiological differentiation inducers. Adipocyte progenitor cells are enriched by immuno-magnetic separation, expanded minimally, and induced for beige adipocyte differentiation with carbaprostacyclin, a stable analogue of the endogenous mediator PGI2.


Assuntos
Tecido Adiposo Branco/citologia , Diferenciação Celular , Separação Imunomagnética , Células-Tronco/citologia , Células-Tronco/metabolismo , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/metabolismo , Animais , Antígenos de Diferenciação , Técnicas de Cultura de Células , Separação Imunomagnética/métodos , Imunofenotipagem/métodos , Camundongos
8.
Biochim Biophys Acta ; 1861(4): 285-93, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26775637

RESUMO

Brite adipocytes recently discovered in humans are of considerable importance in energy expenditure by converting energy excess into heat. This property could be useful in the treatment of obesity, and nutritional aspects are relevant to this important issue. Using hMADS cells as a human cell model which undergoes a white to a brite adipocyte conversion, we had shown previously that arachidonic acid, the major metabolite of the essential nutrient Ω6-linoleic acid, plays a major role in this process. Its metabolites PGE2 and PGF2 alpha inhibit this process via a calcium-dependent pathway, whereas in contrast carbaprostacyclin (cPGI2), a stable analog of prostacyclin, activates white to brite adipocyte conversion. Herein, we show that cPGI2 generates via its cognate cell-surface receptor IP-R, a cyclic AMP-signaling pathway involving PKA activity which in turn induces the expression of UCP1. In addition, cPGI2 activates the pathway of nuclear receptors of the PPAR family, i.e. PPARα and PPARγ, which act separately from IP-R to up-regulate the expression of key genes involved in the function of brite adipocytes. Thus dual pathways are playing in concert for the occurrence of a browning process of human white adipocytes. These results make prostacyclin analogs as a new class of interesting molecules to treat obesity and associated diseases.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Epoprostenol/análogos & derivados , PPAR alfa/agonistas , PPAR gama/agonistas , Receptores de Prostaglandina/agonistas , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Epoprostenol/farmacologia , Humanos , Lactente , Canais Iônicos/genética , Canais Iônicos/metabolismo , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/metabolismo , Fenótipo , Interferência de RNA , Receptores de Epoprostenol , Receptores de Prostaglandina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Fatores de Tempo , Transfecção , Proteína Desacopladora 1
9.
Artigo em Inglês | MEDLINE | ID: mdl-26347713

RESUMO

De novo formation of beige/brite adipocytes from progenitor cells contributes to the thermogenic adaptation of adipose tissue and holds great potential for the therapeutic remodeling of fat as a treatment for obesity. Despite the recent identification of several factors regulating browning of white fat, there is a lack of physiological cell models for the mechanistic investigation of progenitor-mediated beige/brite differentiation. We have previously revealed prostacyclin (PGI2) as one of the few known endogenous extracellular mediators promoting de novo beige/brite formation by relaying ß-adrenergic stimulation to the progenitor level. Here, we present a cell model based on murine primary progenitor cells defined by markers previously shown to be relevant for in vivo browning, including a simplified isolation procedure. We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation. By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype. Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation.

10.
PLoS One ; 10(9): e0138257, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26382271

RESUMO

The MYB transcription factor plays critical roles in normal and malignant haematopoiesis. We previously showed that MYB was a direct activator of FLT3 expression within the context of acute myeloid leukaemia. During normal haematopoiesis, increasing levels of FLT3 expression determine a strict hierarchy within the haematopoietic stem and early progenitor compartment, which associates with lymphoid and myeloid commitment potential. We use the conditional deletion of the Myb gene to investigate the influence of MYB in Flt3 transcriptional regulation within the haematopoietic stem cell (HSC) hierarchy. In accordance with previous report, in vivo deletion of Myb resulted in rapid biased differentiation of HSC with concomitant loss of proliferation capacity. We find that loss of MYB activity also coincided with decreased FLT3 expression. At the chromatin level, the Flt3 promoter is primed in immature HSC, but occupancy of further intronic elements determines expression. Binding to these locations, MYB and C/EBPα need functional cooperation to activate transcription of the locus. This cooperation is cell context dependent and indicates that MYB and C/EBPα activities are inter-dependent in controlling Flt3 expression to influence lineage commitment of multipotential progenitors.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas Oncogênicas v-myb/fisiologia , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Cultivadas , Regulação da Expressão Gênica , Hematopoese/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas v-myb/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
11.
Mol Metab ; 3(9): 834-47, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25506549

RESUMO

OBJECTIVE: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. METHODS/RESULTS: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca(++) signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. CONCLUSION: Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the "browning" process to take place.

12.
PLoS One ; 9(10): e110428, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25313899

RESUMO

Presence of thermogenically active adipose tissue in adult humans has been inversely associated with obesity and type 2 diabetes. While it had been shown that insulin is crucial for the development of classical brown fat, its role in development and function of inducible brown-in-white (brite) adipose tissue is less clear. Here we show that insulin deficiency impaired differentiation of brite adipocytes. However, adrenergic stimulation almost fully induced the thermogenic program under these settings. Although brite differentiation of adipocytes as well as browning of white adipose tissue entailed substantially elevated glucose uptake by adipose tissue, the capacity of insulin to stimulate glucose uptake surprisingly was not higher in the brite state. Notably, in line with the insulin-independent stimulation of glucose uptake, our data revealed that brite recruitment results in induction of solute carrier family 2 (GLUT-1) expression in adipocytes and inguinal WAT. These results for the first time demonstrate that insulin signaling is neither essential for brite recruitment, nor is it improved in cells or tissues upon browning.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Transdução de Sinais , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Diferenciação Celular , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Expressão Gênica , Masculino , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo
13.
Metabolism ; 63(10): 1238-49, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25107565

RESUMO

The identification of active brown fat in humans has evoked widespread interest in the biology of non-shivering thermogenesis among basic and clinical researchers. As a consequence we have experienced a plethora of contributions related to cellular and molecular processes in thermogenic adipocytes as well as their function in the organismal context and their relevance to human physiology. In this review we focus on the cellular basis of non-shivering thermogenesis, particularly in relation to human health and metabolic disease. We provide an overview of the cellular function and distribution of thermogenic adipocytes in mouse and humans, and how this can be affected by environmental factors, such as prolonged cold exposure. We elaborate on recent evidence and open questions on the distinction of classical brown versus beige/brite adipocytes. Further, the origin of thermogenic adipocytes as well as current models for the recruitment of beige/brite adipocytes is discussed with an emphasis on the role of progenitor cells. Focusing on humans, we describe the expanding evidence for the activity, function and physiological relevance of thermogenic adipocytes. Finally, as the potential of thermogenic adipocyte activation as a therapeutic approach for the treatment of obesity and associated metabolic diseases becomes evident, we highlight goals and challenges for current research on the road to clinical translation.


Assuntos
Adipócitos/fisiologia , Termogênese/fisiologia , Tecido Adiposo Marrom/fisiologia , Animais , Meio Ambiente , Humanos , Obesidade/fisiopatologia
14.
Stem Cells ; 32(6): 1578-90, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24375761

RESUMO

Adipose tissue contains thermogenic adipocytes (i.e., brown and brite/beige) that oxidize nutrients at exceptionally high rates via nonshivering thermogenesis. Its recent discovery in adult humans has opened up new avenues to fight obesity and related disorders such as diabetes. Here, we identified miR-26a and -26b as key regulators of human white and brite adipocyte differentiation. Both microRNAs are upregulated in early adipogenesis, and their inhibition prevented lipid accumulation while their overexpression accelerated it. Intriguingly, miR-26a significantly induced pathways related to energy dissipation, shifted mitochondrial morphology toward that seen in brown adipocytes, and promoted uncoupled respiration by markedly increasing the hallmark protein of brown fat, uncoupling protein 1. By combining in silico target prediction, transcriptomics, and an RNA interference screen, we identified the sheddase ADAM metallopeptidase domain 17 (ADAM17) as a direct target of miR-26 that mediated the observed effects on white and brite adipogenesis. These results point to a novel, critical role for the miR-26 family and its downstream effector ADAM17 in human adipocyte differentiation by promoting characteristics of energy-dissipating thermogenic adipocytes.


Assuntos
Adipócitos Marrons/metabolismo , Adipogenia/genética , MicroRNAs/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAM17 , Adipócitos Marrons/citologia , Adipócitos Marrons/ultraestrutura , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/ultraestrutura , Adulto , Diferenciação Celular/genética , Pré-Escolar , Temperatura Baixa , Simulação por Computador , Humanos , Lactente , Canais Iônicos , Masculino , MicroRNAs/genética , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais , Transdução de Sinais/genética , Transcriptoma/genética , Proteína Desacopladora 1 , Regulação para Cima/genética
15.
Cell Metab ; 17(4): 575-85, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23499424

RESUMO

Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional cofactor transducin beta-like-related 1(TBLR1) blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and, when placed on a high-fat-diet, show aggravated adiposity, glucose intolerance, and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFAs). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes might thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders.


Assuntos
Tecido Adiposo Branco/metabolismo , Mobilização Lipídica/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Células 3T3-L1 , Animais , AMP Cíclico/metabolismo , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/sangue , Humanos , Resistência à Insulina , Lipólise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Obesidade/patologia , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais
16.
Cell Metab ; 14(1): 123-30, 2011 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-21723510

RESUMO

Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling.


Assuntos
Ácidos e Sais Biliares/metabolismo , Fígado/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Ácidos e Sais Biliares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Simportadores/antagonistas & inibidores , Simportadores/genética , Simportadores/metabolismo
17.
Diabetes ; 59(8): 1991-2000, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20522600

RESUMO

OBJECTIVE: Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in adipocytes. The pseudokinase tribbles (TRB) 3 has been identified by us and others as a critical regulator of hepatic glucose homeostasis in type 2 diabetes and WAT lipid homeostasis. Therefore, this study aimed to test the hypothesis that the TRB gene family fulfills broader functions in the integration of metabolic and inflammatory pathways in various tissues. RESEARCH DESIGN AND METHODS: To determine the role of TRB family members for WAT function, we profiled the expression patterns of TRB13 under healthy and metabolic stress conditions. The differentially expressed TRB1 was functionally characterized in loss-of-function animal and primary adipocyte models. RESULTS: Here, we show that the expression of TRB1 was specifically upregulated during acute and chronic inflammation in WAT of mice. Deficiency of TRB1 was found to impair cytokine gene expression in white adipocytes and to protect against high-fat diet-induced obesity. In adipocytes, TRB1 served as a nuclear transcriptional coactivator for the nuclear factor kappaB subunit RelA, thereby promoting the induction of proinflammatory cytokines in these cells. CONCLUSIONS: As inflammation is typically seen in sepsis, insulin resistance, and obesity-related type 2 diabetes, the dual role of TRB1 as both a target and a (co) activator of inflammatory signaling might provide a molecular rationale for the amplification of proinflammatory responses in WAT in these subjects.


Assuntos
Tecido Adiposo/fisiopatologia , Inflamação/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Adipócitos/fisiologia , Animais , Linhagem Celular , Cromatina/fisiologia , Primers do DNA , Humanos , Rim/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , RNA/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
18.
Science ; 328(5982): 1158-61, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20448152

RESUMO

Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of beta-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis.


Assuntos
Adipócitos Marrons/fisiologia , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Metabolismo Energético , Prostaglandinas/metabolismo , Termogênese , Adipócitos Marrons/citologia , Adipogenia , Tecido Adiposo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/enzimologia , Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Animais , Peso Corporal , Gorduras na Dieta/administração & dosagem , Dioxóis/farmacologia , Feminino , Regulação Enzimológica da Expressão Gênica , Homeostase , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Norepinefrina/metabolismo , Obesidade/etiologia , Obesidade/prevenção & controle , Consumo de Oxigênio , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais
19.
J Steroid Biochem Mol Biol ; 122(1-3): 10-20, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20170729

RESUMO

Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue-specific contributions of the glucocorticoid pathway to the control of energy metabolism.


Assuntos
Glucocorticoides/metabolismo , Doenças Metabólicas/metabolismo , Receptores de Glucocorticoides/metabolismo , Tecido Adiposo/metabolismo , Animais , Humanos , Fígado/metabolismo , Doenças Metabólicas/genética , Camundongos , Músculo Esquelético/metabolismo
20.
Hepatology ; 50(6): 1963-71, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19821526

RESUMO

UNLABELLED: In mammals, proper maintenance of blood glucose levels within narrow limits is one of the most critical prerequisites for healthy energy homeostasis and body function. Consequently, hyper- and hypoglycemia represent hallmarks of severe metabolic pathologies, including type II diabetes and acute sepsis, respectively. Although the liver plays a crucial role in the control of systemic glucose homeostasis, the molecular mechanisms of aberrant hepatic glucose regulation under metabolic stress conditions remain largely unknown. Here we report the development of a liver-specific adenoviral in vivo system for monitoring promoter activity of the key gluconeogenic enzyme gene phosphoenolpyruvate carboxykinase (PEPCK) in mice. By employing in vivo promoter deletion technology, the glucocorticoid response unit (GRU) and the cyclic adenosine monophosphate (cAMP)-responsive element (CRE) were identified as critical cis-regulatory targets of proinflammatory signaling under septic conditions. In particular, both elements were found to be required for inhibition of PEPCK transcription during sepsis, thereby mediating endotoxic hypoglycemia. Indeed, expression of nuclear receptor cofactor peroxisome proliferator-activator receptor coactivator 1alpha (PGC-1alpha), the molecular mediator of GRU/CRE synergism on the PEPCK promoter, was found to be specifically repressed in septic liver, and restoration of PGC-1alpha in cytokine-exposed hepatocytes blunted the inhibitory effect of proinflammatory signaling on PEPCK gene expression. CONCLUSION: The dysregulation of hormonal synergism through the repression of PGC-1alpha as identified by in vivo promoter monitoring may provide a molecular rationale for hypoglycemia during sepsis, thereby highlighting the importance of hepatic glucose homeostasis for metabolic dysfunction in these patients.


Assuntos
Inflamação/etiologia , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Regiões Promotoras Genéticas , Sepse/metabolismo , Animais , Células Cultivadas , AMP Cíclico/fisiologia , Glucocorticoides/fisiologia , Glucose/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/análise , Elementos de Resposta , Transdução de Sinais , Transativadores/fisiologia , Fatores de Transcrição
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