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1.
bioRxiv ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38370804

RESUMO

Fluorescent biosensors revolutionized biomedical science by enabling the direct measurement of signaling activities in living cells, yet the current technology is limited in resolution and dimensionality. Here, we introduce highly sensitive chemigenetic kinase activity biosensors that combine the genetically encodable self-labeling protein tag HaloTag7 with bright far-red-emitting synthetic fluorophores. This technology enables five-color biosensor multiplexing, 4D activity imaging, and functional super-resolution imaging via stimulated emission depletion (STED) microscopy.

2.
Annu Rev Physiol ; 86: 225-253, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345906

RESUMO

Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.


Assuntos
Exossomos , Doenças Metabólicas , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Doenças Metabólicas/metabolismo
3.
Cell Metab ; 34(7): 978-990.e4, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35700738

RESUMO

Nonalcoholic steatohepatitis (NASH) is a liver disease associated with significant morbidity. Kupffer cells (KCs) produce endogenous miR-690 and, via exosome secretion, shuttle this miRNA to other liver cells, such as hepatocytes, recruited hepatic macrophages (RHMs), and hepatic stellate cells (HSCs). miR-690 directly inhibits fibrogenesis in HSCs, inflammation in RHMs, and de novo lipogenesis in hepatocytes. When an miR-690 mimic is administered to NASH mice in vivo, all the features of the NASH phenotype are robustly inhibited. During the development of NASH, KCs become miR-690 deficient, and miR-690 levels are markedly lower in mouse and human NASH livers than in controls. KC-specific KO of miR-690 promotes NASH pathogenesis. A primary target of miR-690 is NADK mRNA, and NADK levels are inversely proportional to the cellular miR-690 content. These studies show that KCs play a central role in the etiology of NASH and raise the possibility that miR-690 could emerge as a therapeutic for this condition.


Assuntos
Materiais Biomiméticos , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Materiais Biomiméticos/farmacologia , Fibrose , Células de Kupffer/patologia , Células de Kupffer/fisiologia , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/terapia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia
4.
Endocr Rev ; 43(3): 441-468, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35552682

RESUMO

During the last decade, there has been great interest in elucidating the biological role of extracellular vesicles (EVs), particularly, their hormone-like role in cell-to-cell communication. The field of endocrinology is uniquely placed to provide insight into the functions of EVs, which are secreted from all cells into biological fluids and carry endocrine signals to engage in paracellular and distal interactions. EVs are a heterogeneous population of membrane-bound vesicles of varying size, content, and bioactivity. EVs are specifically packaged with signaling molecules, including lipids, proteins, and nucleic acids, and are released via exocytosis into biofluid compartments. EVs regulate the activity of both proximal and distal target cells, including translational activity, metabolism, growth, and development. As such, EVs signaling represents an integral pathway mediating intercellular communication. Moreover, as the content of EVs is cell-type specific, it is a "fingerprint" of the releasing cell and its metabolic status. Recently, changes in the profile of EV and bioactivity have been described in several endocrine-related conditions including diabetes, obesity, cardiovascular diseases, and cancer. The goal of this statement is to highlight relevant aspects of EV research and their potential role in the field of endocrinology.


Assuntos
Endocrinologia , Vesículas Extracelulares , Transporte Biológico , Comunicação Celular/fisiologia , Vesículas Extracelulares/fisiologia , Humanos , Transdução de Sinais
5.
Nat Cell Biol ; 24(6): 954-967, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35637408

RESUMO

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in ß-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in ß-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , MicroRNAs , Animais , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Vesículas Extracelulares/metabolismo , Feminino , Glucose/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Secreção de Insulina , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo
6.
Immunity ; 55(1): 31-55, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021057

RESUMO

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), ß-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.


Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inflamação/imunologia , Obesidade/imunologia , Animais , Humanos , Imunomodulação , Resistência à Insulina
7.
Nat Metab ; 3(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34489604

RESUMO

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16-18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.


Assuntos
Exossomos/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina/genética , Obesidade/metabolismo , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica , Macrófagos/metabolismo , Camundongos , Células Musculares/metabolismo , RNA Interferente Pequeno/genética
8.
Cell Metab ; 33(9): 1744-1762, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34496230

RESUMO

Exosomes are nanoparticles secreted by all cell types and are a large component of the broader class of nanoparticles termed extracellular vesicles (EVs). Once secreted, exosomes gain access to the interstitial space and ultimately the circulation, where they exert local paracrine or distal systemic effects. Because of this, exosomes are important components of an intercellular and intraorgan communication system capable of carrying biologic signals from one cell type or tissue to another. The exosomal cargo consists of proteins, lipids, miRNAs, and other RNA species, and many of the biologic effects of exosomes have been attributed to miRNAs. Exosomal miRNAs have also been used as disease biomarkers. The field of exosome biology and metabolism is rapidly expanding, with new discoveries and reports appearing on a regular basis, and it is possible that potential therapeutic approaches for the use of exosomes or miRNAs in metabolic diseases will be initiated in the near future.


Assuntos
Exossomos , Vesículas Extracelulares , Doenças Metabólicas , MicroRNAs , Comunicação Celular , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Doenças Metabólicas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo
9.
Cell Metab ; 33(4): 781-790.e5, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33450179

RESUMO

Insulin resistance is a major pathophysiologic defect in type 2 diabetes and obesity, while anti-inflammatory M2-like macrophages are important in maintaining normal metabolic homeostasis. Here, we show that M2 polarized bone marrow-derived macrophages (BMDMs) secrete miRNA-containing exosomes (Exos), which improve glucose tolerance and insulin sensitivity when given to obese mice. Depletion of their miRNA cargo blocks the ability of M2 BMDM Exos to enhance insulin sensitivity. We found that miR-690 is highly expressed in M2 BMDM Exos and functions as an insulin sensitizer both in vivo and in vitro. Expressing an miR-690 mimic in miRNA-depleted BMDMs generates Exos that recapitulate the effects of M2 BMDM Exos on metabolic phenotypes. Nadk is a bona fide target mRNA of miR-690, and Nadk plays a role in modulating macrophage inflammation and insulin signaling. Taken together, these data suggest miR-690 could be a new therapeutic insulin-sensitizing agent for metabolic disease.


Assuntos
Exossomos/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Antagomirs/metabolismo , RNA Helicases DEAD-box/deficiência , RNA Helicases DEAD-box/genética , Dieta Hiperlipídica , Hepatócitos/citologia , Hepatócitos/metabolismo , Insulina/metabolismo , Resistência à Insulina , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ribonuclease III/deficiência , Ribonuclease III/genética
10.
Cell Metab ; 31(6): 1173-1188.e5, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32413335

RESUMO

G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.


Assuntos
Insulina/metabolismo , PPAR gama/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Acetatos/farmacologia , Adipócitos/metabolismo , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , PPAR gama/agonistas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/deficiência , Rosiglitazona/farmacologia , Tiramina/análogos & derivados , Tiramina/farmacologia
11.
Cell Metab ; 31(1): 162-173.e5, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31708444

RESUMO

Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPARγ is a master regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones, are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptional co-activator with PDZ-binding motif (TAZ) as a transcriptional co-repressor of PPARγ. We found that adipocyte-specific TAZ knockout (TAZ AKO) mice demonstrate a constitutively active PPARγ state. Obese TAZ AKO mice show improved glucose tolerance and insulin sensitivity compared to littermate controls. PPARγ response genes are upregulated in adipose tissue from TAZ AKO mice and adipose tissue inflammation was also decreased. In vitro and in vivo mechanistic studies revealed that the TAZ-PPARγ interaction is partially dependent on ERK-mediated Ser112 PPARγ phosphorylation. As adipocyte PPARγ Ser112 phosphorylation is increased in obesity, repression of PPARγ activity by TAZ could contribute to insulin resistance. These results identify TAZ as a new factor in the development of obesity-induced insulin resistance.


Assuntos
Adipócitos/metabolismo , Glucose/metabolismo , Resistência à Insulina/genética , PPAR gama/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adipócitos/enzimologia , Adipogenia/genética , Animais , Linhagem Celular , Dieta Hiperlipídica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , PPAR gama/genética , Fosforilação , Transativadores/genética
12.
Nat Rev Endocrinol ; 16(2): 81-90, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836875

RESUMO

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to ß-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive ß-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of ß-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the ß-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on ß-cell function and glycaemia.


Assuntos
Células Secretoras de Insulina/metabolismo , Macrófagos/fisiologia , Obesidade/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Obesidade/imunologia
13.
J Immunol ; 203(12): 3427-3435, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31712385

RESUMO

Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αß and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αß and γδ IEL persistence as obesity progresses with a different mechanism in αß versus γδ IEL populations. CD4+ and CD4+CD8+ αß intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αß and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium-induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.


Assuntos
Colite/etiologia , Colite/metabolismo , Imunomodulação , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Fatores Etários , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Dieta Hiperlipídica , Modelos Animais de Doenças , Imunofluorescência , Regulação da Expressão Gênica , Imuno-Histoquímica , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Masculino , Camundongos , Obesidade/complicações , Receptores CCR/genética , Receptores CCR/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Timo/imunologia , Timo/metabolismo
14.
Nat Metab ; 1(1): 86-97, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528845

RESUMO

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.


Assuntos
Translocador 2 do Nucleotídeo Adenina/deficiência , Adipócitos/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Resistência à Insulina/genética , Obesidade/etiologia , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Animais , Apoptose , Fibrose , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxigênio/metabolismo
15.
Diabetes ; 68(7): 1415-1426, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010956

RESUMO

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Microbiota/fisiologia , Obesidade/metabolismo , Oligopeptídeos/metabolismo , Animais , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Cromatografia Líquida , Dieta Hiperlipídica , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glucose/farmacologia , Intolerância à Glucose , Hibridização in Situ Fluorescente , Insulina/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/induzido quimicamente
16.
J Endocr Soc ; 3(2): 427-445, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30746504

RESUMO

Sirt1 is an NAD-dependent, class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. In this study, we generated mice expressing an enzymatically inactive form (N-MUT) or wild-type (WT) SIRT1 (N-OX) in mature neurons. N-OX male and female mice had impaired glucose tolerance, and N-MUT female, but not male, mice had improved glucose tolerance compared with that of WT littermates. Furthermore, glucose tolerance was improved in all mice with caloric restriction (CR) but was greater in the N-OX mice, who had better glucose tolerance than their littermates. At the reproductive level, N-OX females had impaired estrous cycles, with increased cycle length and more time in estrus. LH and progesterone surges were absent on the evening of proestrus in the N-OX mice, suggesting a defect in spontaneous ovulation, which was confirmed by the ovarian histology revealing fewer corpora lutea. Despite this defect, the mice were still fertile when mated to WT mice on the day of proestrus, indicating that the mice could respond to normal pheromonal or environmental cues. When subjected to CR, the N-OX mice went into diestrus arrest earlier than their littermates. Together, these results suggested that the overexpression of SIRT1 rendered the mice more sensitive to the metabolic improvements and suppression of reproductive cycles by CR, which was independent of circadian rhythms.

17.
Cell Metab ; 29(2): 457-474.e5, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30595478

RESUMO

The nature of obesity-associated islet inflammation and its impact on ß cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating ß cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair ß cell function in a cell-cell contact-dependent manner. Increased engulfment of ß cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote ß cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet ß cells.


Assuntos
Inflamação/imunologia , Células Secretoras de Insulina/metabolismo , Macrófagos/imunologia , Obesidade/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/imunologia , Animais , Linhagem Celular , Proliferação de Células , Secreção de Insulina , Células Secretoras de Insulina/patologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
18.
Mol Metab ; 20: 89-101, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30553772

RESUMO

OBJECTIVE: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand-receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist. METHODS: In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet. RESULTS: CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion. CONCLUSION: These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Quimiocina CX3CL1/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Células Cultivadas , Quimiocina CX3CL1/genética , Fragmentos Fc das Imunoglobulinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/prevenção & controle , Receptores de LDL/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico
19.
J Natl Cancer Inst ; 111(1): 52-59, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30202902

RESUMO

Background: GPR120, a G protein-coupled receptor for long-chain polyunsaturated fatty acids (FAs), mediates the anti-inflammatory effects of omega-3 (ω-3) FAs. We investigated whether host or tumor GPR120 plays a role in the anti-prostate cancer effects of ω-3 FAs. Methods: MycCap prostate cancer allografts were grown in immunocompetent wild-type (WT) and GPR120 knockout (KO) mice fed ω-3 (fish oil) or ω-6 (corn oil) diets. Immune cell infiltration was quantified by flow cytometry, and gene expression of immune cell markers in isolated tumor-associated macrophages (TAMs) was quantified by quantitative real-time polymerase chain reaction. Archived tissue from a fish oil intervention trial was used to correlate gene expression of GPR120 with cell cycle progression (CCP) genes and Ki67 index (n = 11-15 per group). All statistical tests were two-sided. Results: In WT mice (n = 7 per group), dietary ω-3 FAs decreased MycCap allograft tumor growth (mean [SD] final tumor volume ω-6 = 491 [437] mm3 vs ω-3 = 127 [77] mm3, P = .04), whereas in global GPR120KO mice (n = 7 per group) ω-3 FAs had no anticancer effects. Dietary ω-3 FAs inhibited GPR120KO-MycCaP allografts grown in WT mice (n = 8 per group; mean [SD] final tumor volume ω-6 = 776 [767] mm3 vs ω-3 = 36 [34] mm3, P = .02). Omega-3 FA treatment decreased the number of M2-like TAMs in tumor tissue and gene expression of M2 markers in isolated TAMs compared with ω-6 controls in WT (n = 7 per group) but not in GPR120KO mice (n = 7 per group). In human tissue, higher expression of stromal GPR120 correlated with greater reduction in expression of CCP genes in men with prostate cancer on a high-ω-3 diet (r = -.57, P = .04). Conclusions: Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.


Assuntos
Dieta , Ácidos Graxos Ômega-3/antagonistas & inibidores , Macrófagos/patologia , Neoplasias da Próstata/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Animais , Estudos de Casos e Controles , Progressão da Doença , Ácidos Graxos Ômega-3/administração & dosagem , Seguimentos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo
20.
Bioorg Med Chem ; 26(18): 5169-5180, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253886

RESUMO

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
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