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1.
Front Artif Intell ; 4: 749878, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778753

RESUMO

Reinforcement Learning (RL) based machine trading attracts a rich profusion of interest. However, in the existing research, RL in the day-trade task suffers from the noisy financial movement in the short time scale, difficulty in order settlement, and expensive action search in a continuous-value space. This paper introduced an end-to-end RL intraday trading agent, namely QF-TraderNet, based on the quantum finance theory (QFT) and deep reinforcement learning. We proposed a novel design for the intraday RL trader's action space, inspired by the Quantum Price Levels (QPLs). Our action space design also brings the model a learnable profit-and-loss control strategy. QF-TraderNet composes two neural networks: 1) A long short term memory networks for the feature learning of financial time series; 2) a policy generator network (PGN) for generating the distribution of actions. The profitability and robustness of QF-TraderNet have been verified in multi-type financial datasets, including FOREX, metals, crude oil, and financial indices. The experimental results demonstrate that QF-TraderNet outperforms other baselines in terms of cumulative price returns and Sharpe Ratio, and the robustness in the acceidential market shift.

2.
Nat Immunol ; 22(10): 1268-1279, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556885

RESUMO

Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.


Assuntos
Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Adulto , Animais , Peso Corporal/fisiologia , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Células RAW 264.7 , Células THP-1 , Termogênese/fisiologia , Transcrição Genética/fisiologia , Adulto Jovem
3.
Environ Health Perspect ; 127(11): 117003, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31724879

RESUMO

BACKGROUND: Atherosclerotic cardiovascular disease has become the leading cause of death worldwide, and environmental pollutants are increasingly recognized as risk factors for atherosclerosis. Liver X receptors (LXRs) play a central role in atherosclerosis; however, LXR activity of organic pollutants and associated potential risk of atherosclerosis have not yet been characterized. OBJECTIVES: This study aimed to explore whether LXR-antagonistic chemicals are present in indoor house dust and, if so, to characterize this activity in relation to changes in macrophages in vitro and cardiovascular disease indicators in vivo in an atherosclerosis ApoE-/- mouse model. METHODS: We used a His-LXRα-pull-down assay and a nontarget high-resolution mass spectrometry method to screen house dust collected from Chinese homes for LXRα- and LXRß-antagonist activity. A chemical identified in this manner was assessed for its ability to induce cholesterol efflux and foam cell formation in RAW264.7 macrophages, to down-regulate the expression of two LXR-dependent genes, ABCA1 and ABCG1, and finally to induce atherosclerotic lesions in vivo using an ApoE-/- mouse model. RESULTS: We identified the flame retardants triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) in house dust samples and demonstrated their ability to antagonize LXRs. The potency of TPHP was similar to that of the LXR-antagonist SR9238. TPHP could also inhibit cholesterol efflux and promote foam cell formation in RAW264.7 macrophages and mouse peritoneal macrophages and significantly promoted atherosclerotic lesion formation in the ApoE-/- mouse model. CONCLUSIONS: We found LXR-antagonist chemicals in environmental samples of indoor dust from Chinese homes. One of the chemicals, TPHP, was able to promote the development of atherosclerotic lesions in the ApoE-/- mouse model. These results highlight the need to assess the LXR-antagonist activities of pollutants in future environmental management programs. https://doi.org/10.1289/EHP5039.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Aterosclerose/fisiopatologia , Poeira/análise , Animais , Aterosclerose/induzido quimicamente , China , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Células RAW 264.7
4.
Nat Immunol ; 18(5): 519-529, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28346409

RESUMO

Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1f/f; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1f/f; Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/patologia , Endorribonucleases/metabolismo , Macrófagos/fisiologia , Obesidade/imunologia , /metabolismo , Animais , Diferenciação Celular/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Endorribonucleases/genética , Metabolismo Energético/genética , Humanos , Ativação de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , /genética
5.
Sci China Life Sci ; 59(12): 1232-1240, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27837402

RESUMO

The prevalence of obesity and type 2 diabetes is escalating to an epidemic proportion worldwide. Obesity is known to be associated with a state of chronic, low-grade inflammation. Emerging lines of evidence have shown that both innate and adaptive immune responses play crucial roles in the control of metabolic homeostasis. Macrophages in adipose tissues are the essential effector cells in orchestrating metabolic inflammation, which is thought to promote the pathogenic progression of obesity and obesity-related disorders. Here we discuss our current understanding of the distinct modes of activation of adipose tissue macrophages, which can sense the metabolic cues and exert profound effects upon adipose homeostasis. Targeting macrophages in adipose tissues may provide new avenues for developing immunomodulation-based therapeutics against obesity and obesity-associated metabolic diseases.


Assuntos
Tecido Adiposo/imunologia , Homeostase/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Adipócitos/imunologia , Tecido Adiposo/metabolismo , Animais , Humanos , Inflamação/metabolismo , Ativação de Macrófagos/imunologia , Modelos Imunológicos , Obesidade/imunologia , Obesidade/metabolismo
6.
Cell Metab ; 23(1): 165-78, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26549485

RESUMO

Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.


Assuntos
Aterosclerose/imunologia , Exposição Ambiental , Resistência à Insulina/imunologia , Imunidade Adaptativa , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/patologia , Animais , Aorta Torácica/imunologia , Aorta Torácica/patologia , Apolipoproteínas E/genética , Aterosclerose/etiologia , Dieta Hiperlipídica/efeitos adversos , Abrigo para Animais , Imunidade Inata , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Cell ; 160(1-2): 74-87, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25543153

RESUMO

Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP:


Assuntos
Tecido Adiposo Marrom/metabolismo , Linfócitos/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Proliferação de Células , Feminino , Interleucina-13/metabolismo , Interleucina-33 , Interleucinas/imunologia , Linfócitos/citologia , Masculino , Camundongos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Interleucina-4/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo
8.
Cell ; 157(6): 1292-1308, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-24906148

RESUMO

Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Adipócitos Marrons/metabolismo , Animais , Catecolaminas/metabolismo , Temperatura Baixa , Interleucina-13/genética , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Obesidade/metabolismo , Receptores CCR2/metabolismo , Fator de Transcrição STAT6/metabolismo , Termogênese
9.
Nat Commun ; 5: 3528, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24670948

RESUMO

Although the mammalian IRE1α-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1α signalling in vivo remains poorly understood. Here we show that hepatic IRE1α functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1α-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1α results in impairment of fatty acid ß-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1α null mice. XBP1s directly binds to and activates the promoter of PPARα, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1α promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial ß-oxidation and ketogenesis through the XBP1s-PPARα axis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Endorribonucleases/metabolismo , PPAR alfa/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Adaptação Fisiológica , Análise de Variância , Animais , Células Cultivadas , Proteínas de Ligação a DNA/genética , Endorribonucleases/genética , Jejum/sangue , Jejum/metabolismo , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Glucose/metabolismo , Células HEK293 , Humanos , Immunoblotting , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , PPAR alfa/genética , Fatores de Transcrição de Fator Regulador X , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Proteína 1 de Ligação a X-Box
10.
Nat Med ; 20(2): 175-83, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24441829

RESUMO

Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8(-/-)) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvß3 integrin- and αvß5 integrin-dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.


Assuntos
Antígenos de Superfície/metabolismo , Gorduras na Dieta/farmacocinética , Ácidos Graxos/farmacocinética , Proteínas do Leite/metabolismo , Obesidade/genética , Células 3T3-L1 , Análise de Variância , Animais , Antígenos de Superfície/genética , Glicemia/metabolismo , Western Blotting , Composição Corporal/fisiologia , Radioisótopos de Carbono/metabolismo , Fracionamento Celular , Primers do DNA/genética , Gorduras na Dieta/metabolismo , Ácidos Graxos/sangue , Citometria de Fluxo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Knockout , Análise em Microsséries , Microscopia Confocal , Proteínas do Leite/genética , Complexos Multiproteicos/metabolismo , Obesidade/metabolismo , Ácido Oleico/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinases TOR/metabolismo , Triglicerídeos/metabolismo
11.
Blood ; 122(19): 3263-7, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24065242

RESUMO

The rise of obesity and its attendant pathological sequelae, including type 2 diabetes and coronary artery disease, constitute an ongoing public health catastrophe in both the developed and, more recently, the developing world. Although the underlying pathophysiology is complex, chronic low-grade inflammation has emerged as a central driver of both primary metabolic dysfunction and subsequent tissue failure. Importantly, this inflammation has been shown to arise as a consequence of both the disruption of homeostatic tissue resident leukocytes and the recruitment of antagonistic effector cells from the circulation. In this review, we discuss the roles of visceral adipose tissue's salient leukocyte lineages in the transition to obesity and highlight key points at which this emerging immune axis may be manipulated for therapeutic effect.


Assuntos
Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/patologia , Gordura Intra-Abdominal/patologia , Leucócitos/patologia , Obesidade/patologia , Movimento Celular , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/imunologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/imunologia , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/patologia , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Leucócitos/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Obesidade/complicações , Obesidade/imunologia
12.
Science ; 341(6153): 1483-8, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-23970558

RESUMO

Circadian clocks have evolved to regulate physiologic and behavioral rhythms in anticipation of changes in the environment. Although the molecular clock is present in innate immune cells, its role in monocyte homeostasis remains unknown. Here, we report that Ly6C(hi) inflammatory monocytes exhibit diurnal variation, which controls their trafficking to sites of inflammation. This cyclic pattern of trafficking confers protection against Listeria monocytogenes and is regulated by the repressive activity of the circadian gene Bmal1. Accordingly, myeloid cell-specific deletion of Bmal1 induces expression of monocyte-attracting chemokines and disrupts rhythmic cycling of Ly6C(hi) monocytes, predisposing mice to development of pathologies associated with acute and chronic inflammation. These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6C(hi) monocyte numbers.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos/imunologia , Ritmo Circadiano/imunologia , Inflamação/imunologia , Monócitos/imunologia , Fatores de Transcrição ARNTL/genética , Animais , Antígenos Ly/imunologia , Quimiocinas/genética , Quimiotaxia/genética , Quimiotaxia/imunologia , Relógios Circadianos/genética , Ritmo Circadiano/genética , Regulação da Expressão Gênica , Inflamação/genética , Listeria monocytogenes/imunologia , Listeria monocytogenes/patogenicidade , Listeriose/genética , Listeriose/imunologia , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/metabolismo
13.
Nature ; 480(7375): 104-8, 2011 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-22101429

RESUMO

All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the ß(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.


Assuntos
Catecolaminas/metabolismo , Ativação de Macrófagos , Macrófagos/fisiologia , Estresse Fisiológico/fisiologia , Termogênese/fisiologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Temperatura Corporal/genética , Células Cultivadas , Temperatura Baixa , Metabolismo Energético , Regulação da Expressão Gênica , Humanos , Interleucina-4 , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células U937
14.
Proc Natl Acad Sci U S A ; 108(38): 15852-7, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21911379

RESUMO

The endoplasmic reticulum (ER)-resident protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. Here we show that mammalian IRE1α in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1α at Ser(724), a highly conserved site within the kinase activation domain. Blocking Ser(724) phosphorylation impaired the ability of IRE1α to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1α was highly phosphorylated at Ser(724) by PKA in mice with obesity, and silencing hepatic IRE1α markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1α integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Endorribonucleases/metabolismo , Glucagon/farmacologia , Glucose/metabolismo , /metabolismo , Animais , Sequência de Bases , Proteínas Quinases Dependentes de AMP Cíclico/genética , Citoplasma/metabolismo , Retículo Endoplasmático/metabolismo , Endorribonucleases/genética , Perfilação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Immunoblotting , Fígado/citologia , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Obesidade/genética , Obesidade/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina/genética , Serina/metabolismo
15.
PLoS One ; 6(6): e21759, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21738790

RESUMO

SIRT1 plays crucial roles in glucose and lipid metabolism, and has various functions in different tissues including brain. The brain-specific SIRT1 knockout mice display defects in somatotropic signaling, memory and synaptic plasticity. And the female mice without SIRT1 in POMC neuron are more sensitive to diet-induced obesity. Here we created transgenic mice overexpressing SIRT1 in striatum and hippocampus under the control of CaMKIIα promoter. These mice, especially females, exhibited increased fat accumulation accompanied by significant upregulation of adipogenic genes in white adipose tissue. Glucose tolerance of the mice was also impaired with decreased Glut4 mRNA levels in muscle. Moreover, the SIRT1 overexpressing mice showed decreased energy expenditure, and concomitantly mitochondria-related genes were decreased in muscle. In addition, these mice showed unusual spontaneous physical activity pattern, decreased activity in open field and rotarod performance. Further studies demonstrated that SIRT1 deacetylated IRS-2, and upregulated phosphorylation level of IRS-2 and ERK1/2 in striatum. Meanwhile, the neurotransmitter signaling in striatum and the expression of endocrine hormones in hypothalamus and serum T3, T4 levels were altered. Taken together, our findings demonstrate that SIRT1 in forebrain regulates lipid/glucose metabolism and motor function.


Assuntos
Glucose/metabolismo , Metabolismo dos Lipídeos/fisiologia , Prosencéfalo/metabolismo , Sirtuína 1/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Feminino , Hipocampo/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Sirtuína 1/genética , Tiroxina/sangue , Tiroxina/metabolismo , Tri-Iodotironina/sangue , Tri-Iodotironina/metabolismo
16.
Sci Signal ; 3(106): ra7, 2010 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-20103773

RESUMO

Autophosphorylation of inositol-requiring enzyme 1alpha (IRE1alpha) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic beta cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1alpha in a glucose-stimulated or endoplasmic reticulum (ER) stress-responsive manner in pancreatic beta cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. Moreover, IRE1alpha activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1alpha signaling pathway in pancreatic beta cells.


Assuntos
Endorribonucleases/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Glucose/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Endorribonucleases/genética , Feminino , Proteínas de Ligação ao GTP/genética , Células HT29 , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multiproteicos/metabolismo , Proteínas de Neoplasias/genética , Obesidade Mórbida/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores de Quinase C Ativada , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Técnicas do Sistema de Duplo-Híbrido
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