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1.
Immunity ; 50(1): 13-15, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650372

RESUMO

The role of the immune system in homeostasis of pancreatic ß cells in type 2 diabetes mellitus is poorly characterized. In a recent issue of Cell Metabolism, Ying et al. (2018) report that two subpopulations of macrophages expand during obesity to impair ß cell function.


Assuntos
Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Proliferação de Células , Humanos , Inflamação , Insulina , Macrófagos , Obesidade
2.
Nature ; 600(7888): 314-318, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34819664

RESUMO

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.


Assuntos
Adipócitos/metabolismo , Metabolismo Energético , Interleucina-27/metabolismo , Termogênese , Animais , Cirurgia Bariátrica , Modelos Animais de Doenças , Feminino , Humanos , Resistência à Insulina , Interleucina-27/sangue , Interleucina-27/uso terapêutico , Masculino , Camundongos , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/prevenção & controle , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores de Interleucina/metabolismo , Transdução de Sinais , Proteína Desacopladora 1/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Nature ; 550(7674): 119-123, 2017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28953873

RESUMO

Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Envelhecimento/metabolismo , Catecolaminas/metabolismo , Inflamassomos/metabolismo , Lipólise , Macrófagos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Caspase 1/metabolismo , Catecolaminas/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 3 de Diferenciação de Crescimento/deficiência , Fator 3 de Diferenciação de Crescimento/genética , Fator 3 de Diferenciação de Crescimento/metabolismo , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Lipólise/genética , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Norepinefrina/metabolismo , Esterol Esterase/metabolismo
4.
Proc Natl Acad Sci U S A ; 114(43): E9172-E9180, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29073114

RESUMO

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.


Assuntos
Hipotireoidismo/complicações , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Modelos Animais de Doenças , Hipotireoidismo/etiologia , Insulina/metabolismo , Secreção de Insulina , Metabolismo dos Lipídeos , Lipólise/fisiologia , Fígado/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Simportadores/genética
6.
J Clin Invest ; 133(19)2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37781916

RESUMO

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamassomos/genética , Inflamassomos/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/metabolismo , Osteonectina/genética , Osteonectina/metabolismo
7.
Cell Metab ; 30(6): 1024-1039.e6, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31735593

RESUMO

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.


Assuntos
Tecido Adiposo , Envelhecimento/metabolismo , Linfócitos B , Homeostase , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Regulação da Temperatura Corporal , Resposta ao Choque Frio , Feminino , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lipólise , Masculino , Camundongos , Receptores de Interleucina-1/metabolismo
8.
Cell Rep ; 19(2): 225-234, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28402847

RESUMO

In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype.


Assuntos
Resistência à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Macrófagos/imunologia , Infecções por Strongylida/imunologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Diferenciação Celular/imunologia , Dieta Hiperlipídica , Resistência à Insulina/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Interleucina-4/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Nippostrongylus/patogenicidade , Fagocitose/genética , Transdução de Sinais/imunologia , Infecções por Strongylida/metabolismo , Infecções por Strongylida/parasitologia
9.
Cell Rep ; 14(7): 1571-1580, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26876170

RESUMO

The hallmarks of age-related immune senescence are chronic inflammation, aberrant expansion of effector memory, and loss of naive T lymphocytes due in part to systemic activation of innate immune sensor NLRP3 inflammasome in myeloid lineage cells. The endogenous mechanisms that regulate inflammasome activation during aging are unknown. Here, we present evidence that growth hormone receptor (GH-R)-dependent downregulation of NLRP3 inflammasome in macrophages is linked to pro-longevity effects that maintain immune system homeostasis in aging. Deletion of GH-R prevented the macrophage-driven age-related activation of inflammasome in response to NLRP3 ligands and also increased the preservation of naive T cells, even in advanced age and with higher IFNγ secretion from effector cells. The mechanism of inflammasome inhibition is linked to autocrine somatotropic axis as ablation of IGF1R in macrophages lowered the NLRP3 inflammasome activation. Together, our findings show that functional somatotropic axis in macrophages controls inflammation, thus linking NLRP3-mediated innate immune signaling to health span and longevity.


Assuntos
Envelhecimento/genética , Proteínas de Transporte/genética , Inflamassomos/genética , Macrófagos/imunologia , Receptor IGF Tipo 1/genética , Receptores da Somatotropina/genética , Envelhecimento/imunologia , Animais , Comunicação Autócrina , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Proteínas de Transporte/imunologia , Regulação da Expressão Gênica , Homeostase/imunologia , Imunidade Inata , Memória Imunológica , Inflamassomos/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Longevidade/genética , Longevidade/imunologia , Macrófagos/citologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptor IGF Tipo 1/deficiência , Receptor IGF Tipo 1/imunologia , Receptores da Somatotropina/deficiência , Receptores da Somatotropina/imunologia , Transdução de Sinais , Baço/citologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
10.
Thyroid ; 23(4): 488-96, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23078112

RESUMO

BACKGROUND: Organogenesis of the thyroid gland requires the Pax8 protein. Absence or reduction of Pax8 results in congenital hypothyroidism in animal models and humans, respectively. This study aims at elucidating the regulatory mechanism leading to the expression of Pax8 in thyroid cells. METHODS: The murine Pax8 gene promoter was functionally dissected by mutagenesis and transfection in the thyroid cell line FRTL-5. Nuclear factors important for thyroid-specific gene expression were identified by DNA-binding assays. RESULTS: We show that Pax8 binds to and controls the expression of its own promoter. Furthermore, we identify a novel, thyroid-specific, DNA-binding activity (denominated nTTF [for novel Thyroid Transcription Factor]) that recognizes a specific region of the Pax8 promoter. CONCLUSIONS: The Pax8 promoter appears to be autoregulated, a feature that might be responsible for the haploinsufficiency displayed by this gene.


Assuntos
Homeostase/genética , Fatores de Transcrição Box Pareados/genética , Regiões Promotoras Genéticas , Glândula Tireoide/metabolismo , Animais , Sítios de Ligação/genética , Camundongos , Mutagênese , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados/metabolismo , Ativação Transcricional
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