Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Metab ; 6(4): 708-723, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38499763

RESUMO

Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gßγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.


Assuntos
Caquexia , Ácido Láctico , Neoplasias , Receptores Acoplados a Proteínas G , Caquexia/metabolismo , Caquexia/etiologia , Animais , Receptores Acoplados a Proteínas G/metabolismo , Camundongos , Humanos , Ácido Láctico/metabolismo , Masculino , Feminino , Neoplasias/metabolismo , Neoplasias/complicações , Transdução de Sinais
2.
Immunity ; 57(3): 513-527.e6, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38262419

RESUMO

Accumulation of senescent cells in organs and tissues is a hallmark of aging and known to contribute to age-related diseases. Although aging-associated immune dysfunction, or immunosenescence, is known to contribute to this process, the underlying mechanism remains elusive. Here, we report that type 2 cytokine signaling deficiency accelerated aging and, conversely, that the interleukin-4 (IL-4)-STAT6 pathway protected macrophages from senescence. Mechanistically, activated STAT6 promoted the expression of genes involved in DNA repair both via homologous recombination and Fanconi anemia pathways. Conversely, STAT6 deficiency induced release of nuclear DNA into the cytoplasm to promote tissue inflammation and organismal aging. Importantly, we demonstrate that IL-4 treatment prevented macrophage senescence and improved the health span of aged mice to an extent comparable to senolytic treatment, with further additive effects when combined. Together, our findings support that type 2 cytokine signaling protects macrophages from immunosenescence and thus hold therapeutic potential for improving healthy aging.


Assuntos
Senescência Celular , Interleucina-4 , Animais , Camundongos , Interleucina-4/metabolismo , Envelhecimento/genética , Macrófagos , Inflamação
3.
Nat Commun ; 14(1): 7102, 2023 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-37925548

RESUMO

Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPß for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPß-mediated S100b expression.


Assuntos
Tecido Adiposo Bege , Fatores de Transcrição , Camundongos , Animais , Tecido Adiposo Bege/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Marrom/metabolismo , Termogênese/genética
4.
Trends Cell Biol ; 33(3): 182-184, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36517314

RESUMO

The mitochondrial calcium uniporter (MCU) controls mitochondrial bioenergetics, and its activity varies greatly between tissues. Here, we highlight a recently identified MCU-EMRE-UCP1 complex, named thermoporter, in the adaptive thermogenesis of brown adipose tissue (BAT). The thermoporter enhances MCU activity to promote thermogenic metabolism, demonstrating a BAT-specific regulation for MCU activity.


Assuntos
Canais de Cálcio , Mitocôndrias , Humanos , Canais de Cálcio/metabolismo , Mitocôndrias/metabolismo , Membrana Celular/metabolismo , Cálcio/metabolismo
5.
Nat Commun ; 13(1): 6030, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229481

RESUMO

Fibrosis disrupts adipose tissue (AT) homeostasis and exacerbates metabolic dysfunction upon chronic caloric excess. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFß signaling to orchestrate a cellular and/or functional shift of adipocytes from energy storage to extracellular matrix (ECM) remodeling in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4- myofibroblasts upon TGFß stimulation. On the other hand, Hippo pathway inhibition during obesity impaired adipocyte identity while promoted ECM remodeling activity of adipocytes. Macrophages recruited by CCL2 produced TGFß to accelerate AT fibrosis. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Via de Sinalização Hippo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Dipeptidil Peptidase 4/metabolismo , Fibrose , Camundongos , Proteínas Serina-Treonina Quinases/genética , Fator de Crescimento Transformador beta/metabolismo
6.
Front Immunol ; 13: 977485, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119080

RESUMO

Adipose tissue macrophage (ATM) has been appreciated for its critical contribution to obesity-associated metabolic diseases in recent years. Here, we discuss the regulation of ATM on both metabolic homeostatsis and dysfunction. In particular, the macrophage polarization and recruitment as well as the crosstalk between ATM and adipocyte in thermogenesis, obesity, insulin resistance and adipose tissue fibrosis have been reviewed. A better understanding of how ATM regulates adipose tissue remodeling may provide novel therapeutic strategies against obesity and associated metabolic diseases.


Assuntos
Inflamação , Resistência à Insulina , Tecido Adiposo/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo
7.
Cell Metab ; 34(9): 1325-1341.e6, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-35977541

RESUMO

Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a "thermoporter" that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.


Assuntos
Tecido Adiposo Marrom , Cálcio , Tecido Adiposo Marrom/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio , Mamíferos/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Termogênese/fisiologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
8.
STAR Protoc ; 3(3): 101480, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35755124

RESUMO

The communication between macrophage and adipocyte plays a critical role in the initiation and development of metabolic inflammation, which is difficult to study in vivo. Here, we provide a step-by-step protocol using differentiated cells to investigate the paracrine effects of classically activated macrophage on beige adipocyte metabolism in vitro. This protocol uses bone-marrow-derived macrophage and SVF-derived UCP1+ beige adipocyte in a culture model to study immune regulation of adipocyte metabolism by western blot analyses. For complete details on the use and execution of this protocol, please refer to Yao et al. (2021).


Assuntos
Adipócitos Bege , Adipócitos/metabolismo , Animais , Diferenciação Celular , Macrófagos , Camundongos , Termogênese
9.
STAR Protoc ; 3(4): 101895, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36595932

RESUMO

The classical Cre-LoxP system is time consuming. Here we detail a protocol that leverages Rosa26-LSL-Cas9;Adiponectin-Cre mice to restrict Cas9 expression in adipocytes. This enables specific deletion of target genes in brown adipocytes within 6 weeks by local injection of AAV-sgRNA into interscapular brown adipose tissue. We also describe an adiponectin-promoter-driven AAV vector to express sgRNA-resistant cDNA-encoded protein for subsequent rescue. This protocol thus provides an efficient means to specifically knockout and overexpress genes in brown adipocytes in vivo. For complete details on the use and execution of this protocol, please refer to Xue et al. (2022).1.


Assuntos
Adipócitos Marrons , Adiponectina , Camundongos , Animais , Adipócitos Marrons/metabolismo , Técnicas de Inativação de Genes , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Marrom/metabolismo , Regiões Promotoras Genéticas
10.
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.

11.
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 Gênica/fisiologia , Adulto Jovem
12.
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
13.
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 , Proteínas Serina-Treonina Quinases/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 , Proteínas Serina-Treonina Quinases/genética
14.
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
15.
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
16.
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
17.
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
18.
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 , Proteínas Serina-Treonina Quinases/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 , Proteínas Serina-Treonina Quinases/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
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...