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1.
Cell ; 156(3): 495-509, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24462248

RESUMO

Maternal metabolic homeostasis exerts long-term effects on the offspring's health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.


Assuntos
Dieta Hiperlipídica , Hiperglicemia/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Lactação , Obesidade/metabolismo , Animais , Axônios/metabolismo , Feminino , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Gravidez , Pró-Opiomelanocortina/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais
2.
Nat Immunol ; 15(5): 423-30, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24681566

RESUMO

Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6ra(Δmyel) mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra(Δmyel) mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.


Assuntos
Endotoxemia/imunologia , Resistência à Insulina , Interleucina-6/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Obesidade/imunologia , Animais , Células Cultivadas , Humanos , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Interleucina-4/imunologia , Interleucina-6/genética , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Receptores de Interleucina-6/genética , Transdução de Sinais/genética
3.
Science ; 384(6694): 438-446, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38662831

RESUMO

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.


Assuntos
Alimentos , Gluconeogênese , Glucose , Fígado , Proteínas de Membrana , Mitocôndrias Hepáticas , Dinâmica Mitocondrial , Proteínas Mitocondriais , Percepção , Animais , Masculino , Camundongos , Técnicas de Introdução de Genes , Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Neurônios/metabolismo , Fosforilação , Pró-Opiomelanocortina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos
4.
Nat Metab ; 3(12): 1662-1679, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34931084

RESUMO

Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Células Ependimogliais/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Proteína Relacionada com Agouti/química , Animais , Biomarcadores , Barreira Hematoencefálica/metabolismo , Cálcio , Metabolismo Energético , Imunofluorescência , Grelina/metabolismo , Glucose/metabolismo , Resistência à Insulina , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Modelos Biológicos , Fragmentos de Peptídeos/metabolismo , Receptor de Insulina/metabolismo
5.
Nat Commun ; 12(1): 5249, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475397

RESUMO

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.


Assuntos
Glucose/metabolismo , Obesidade/metabolismo , Receptores de Orexina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Homeostase , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Resistência à Insulina , Fígado/metabolismo , Camundongos , Fibras Nervosas/metabolismo , Obesidade/etiologia , Receptores de Orexina/genética , Orexinas/metabolismo , Núcleos da Rafe/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais
6.
Cell Rep ; 25(2): 383-397.e10, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304679

RESUMO

Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity.


Assuntos
Ácidos Graxos/metabolismo , Glucose/metabolismo , Homeostase , Mitocôndrias/patologia , Neurônios/metabolismo , Obesidade/prevenção & controle , Fosforilação Oxidativa , Pró-Opiomelanocortina/metabolismo , Animais , Fator de Indução de Apoptose/fisiologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Intolerância à Glucose , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/metabolismo , Neurônios/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia
7.
Cell Rep ; 17(10): 2512-2521, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27926856

RESUMO

Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IRΔMCH) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IRΔMCH mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.


Assuntos
Hormônios Hipotalâmicos/genética , Resistência à Insulina/genética , Insulina/metabolismo , Melaninas/genética , Obesidade/metabolismo , Hormônios Hipofisários/genética , Animais , Dieta Hiperlipídica , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Humanos , Hipotálamo/metabolismo , Insulina/administração & dosagem , Locomoção/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Obesidade/tratamento farmacológico , Obesidade/patologia , Fosfatidilinositol 3-Quinases/genética
8.
Cell Metab ; 18(3): 445-55, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-24011078

RESUMO

Brown adipose tissue (BAT) is a critical regulator of glucose, lipid, and energy homeostasis, and its activity is tightly controlled by the sympathetic nervous system. However, the mechanisms underlying CNS-dependent control of BAT sympathetic nerve activity (SNA) are only partly understood. Here, we demonstrate that catecholaminergic neurons in the locus coeruleus (LC) adapt their firing frequency to extracellular glucose concentrations in a K(ATP)-channel-dependent manner. Inhibiting K(ATP)-channel-dependent control of neuronal activity via the expression of a variant K(ATP) channel in tyrosine-hydroxylase-expressing neurons and in neurons of the LC enhances diet-induced obesity in mice. Obesity results from decreased energy expenditure, lower steady-state BAT SNA, and an attenuated ability of centrally applied glucose to activate BAT SNA. This impairs the thermogenic transcriptional program of BAT. Collectively, our data reveal a role of K(ATP)-channel-dependent neuronal excitability in catecholaminergic neurons in maintaining thermogenic BAT sympathetic tone and energy homeostasis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Neurônios Colinérgicos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Sistema Nervoso Simpático/metabolismo , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Dieta Hiperlipídica , Metabolismo Energético/efeitos dos fármacos , Glucose/farmacologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Obesidade/etiologia , Obesidade/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Tirosina 3-Mono-Oxigenase/metabolismo
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