Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Sci Adv ; 8(42): eabo5555, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36269831

RESUMO

Maladaptive insulin signaling is a key feature in the pathogenesis of severe metabolic disorders, including obesity and diabetes. Enhancing insulin sensitivity represents a major goal in the treatment of patients affected by diabetes. Here, we identify transforming growth factor-ß1 stimulated clone 22 D4 (TSC22D4) as a novel interaction partner for protein kinase B/Akt1, a critical mediator of insulin/phosphatidylinositol 3-kinase signaling pathway. While energy deprivation and oxidative stress promote the TSC22D4-Akt1 interaction, refeeding mice or exposing cells to glucose and insulin impairs this interaction, which relies on an intrinsically disordered region (D2 domain) within TSC22D4. Functionally, the interaction with TSC22D4 reduces basal phosphorylation of Akt and its downstream targets during starvation, thereby promoting insulin sensitivity. Genetic, liver-specific reconstitution experiments in mice demonstrate that the interaction between TSC22D4 and Akt1 improves glucose handling and insulin sensitivity. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate insulin signaling and glucose metabolism.


Assuntos
Resistência à Insulina , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Glucose/metabolismo , Insulina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição , Fator de Crescimento Transformador beta1
2.
Nat Commun ; 12(1): 2999, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016966

RESUMO

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteínas de Membrana/metabolismo , Estado Pré-Diabético/metabolismo , Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo Branco/citologia , Adolescente , Adulto , Idoso , Animais , Células CHO , Estudos de Coortes , Cricetulus , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Insulina/metabolismo , Resistência à Insulina , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Células NIH 3T3 , Estado Pré-Diabético/sangue , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/etiologia , Cultura Primária de Células , Proteínas/análise , Receptores Acoplados a Proteínas G/sangue , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Adulto Jovem
3.
Life Sci Alliance ; 4(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33536239

RESUMO

Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.


Assuntos
Metabolismo Energético , Secreção de Insulina , Lipocalinas/genética , Lipocalinas/metabolismo , Animais , Biomarcadores , Imunofluorescência , Expressão Gênica , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Metabolismo dos Lipídeos , Lipocalinas/sangue , Fígado/metabolismo , Masculino , Camundongos , Obesidade/etiologia , Obesidade/metabolismo
4.
Immunity ; 52(6): 1075-1087.e8, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32445619

RESUMO

Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor HIF-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a-/- NK cells. Extended culture with an HIF-1α inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.


Assuntos
Citotoxicidade Imunológica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Animais , Biomarcadores , Biologia Computacional , Citocinas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/mortalidade , Prognóstico , Análise de Célula Única , Transcriptoma , Microambiente Tumoral/imunologia
5.
Mol Cell Proteomics ; 17(10): 1909-1921, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29980615

RESUMO

Seasonal epidemics of influenza A virus are a major cause of severe illness and are of high socio-economic relevance. For the design of effective antiviral therapies, a detailed knowledge of pathways perturbed by virus infection is critical. We performed comprehensive expression and organellar proteomics experiments to study the cellular consequences of influenza A virus infection using three human epithelial cell lines derived from human lung carcinomas: A549, Calu-1 and NCI-H1299. As a common response, the type I interferon pathway was up-regulated upon infection. Interestingly, influenza A virus infection led to numerous cell line-specific responses affecting both protein abundance as well as subcellular localization. In A549 cells, the vesicular compartment appeared expanded after virus infection. The composition of autophagsomes was altered by targeting of ribosomes, viral mRNA and proteins to these double membrane vesicles. Thus, autophagy may support viral protein translation by promoting the clustering of the respective molecular machinery in autophagosomes in a cell line-dependent manner.


Assuntos
Autofagossomos/metabolismo , Vírus da Influenza A/metabolismo , Proteínas Ribossômicas/metabolismo , Autofagia , Linhagem Celular Tumoral , Humanos , Influenza Humana/metabolismo , Influenza Humana/patologia , Influenza Humana/virologia , Proteoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Ribossomos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA