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1.
Elife ; 72018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30230471

RESUMO

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.


Assuntos
Glucose/metabolismo , Insulina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipotálamo/citologia , Insulina/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Plasticidade Neuronal/genética , Pró-Opiomelanocortina/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo
2.
Diabetes ; 67(7): 1246-1257, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29712668

RESUMO

Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp-Cre;Ptpn2fl/fl ) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [14C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre;Ptpn2fl/fl mice was corrected by IR heterozygosity (Agrp-Cre;Ptpn2fl/fl ;Insrfl/+ ), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Ingestão de Alimentos/fisiologia , Gluconeogênese/genética , Glucose/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/fisiologia , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo dos Carboidratos/fisiologia , Metabolismo Energético/genética , Jejum , Técnica Clamp de Glucose , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Receptor de Insulina/metabolismo , Transdução de Sinais/genética
3.
Mol Metab ; 5(11): 1083-1091, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27818934

RESUMO

OBJECTIVE: The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle. METHODS: Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined. RESULTS: We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOSµ partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOSµ/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake. CONCLUSIONS: We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism.


Assuntos
Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Músculo Esquelético/metabolismo , Animais , Glucose-6-Fosfato , Humanos , Insulina , Resistência à Insulina , Camundongos , Fibras Musculares Esqueléticas , Óxido Nítrico
5.
Am J Physiol Endocrinol Metab ; 310(10): E838-45, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27006199

RESUMO

Nitric oxide influences intramuscular signaling that affects skeletal muscle glucose uptake during exercise. The role of the main NO-producing enzyme isoform activated during skeletal muscle contraction, neuronal nitric oxide synthase-µ (nNOSµ), in modulating glucose uptake has not been investigated in a physiological exercise model. In this study, conscious and unrestrained chronically catheterized nNOSµ(+/+) and nNOSµ(-/-) mice either remained at rest or ran on a treadmill at 17 m/min for 30 min. Both groups of mice demonstrated similar exercise capacity during a maximal exercise test to exhaustion (17.7 ± 0.6 vs. 15.9 ± 0.9 min for nNOSµ(+/+) and nNOSµ(-/-), respectively, P > 0.05). Resting and exercise blood glucose levels were comparable between the genotypes. Very low levels of NOS activity were detected in skeletal muscle from nNOSµ(-/-) mice, and exercise increased NOS activity only in nNOSµ(+/+) mice (4.4 ± 0.3 to 5.2 ± 0.4 pmol·mg(-1)·min(-1), P < 0.05). Exercise significantly increased glucose uptake in gastrocnemius muscle (5- to 7-fold) and, surprisingly, more so in nNOSµ(-/-) than in nNOSµ(+/+) mice (P < 0.05). This is in parallel with a greater increase in AMPK phosphorylation during exercise in nNOSµ(-/-) mice. In conclusion, nNOSµ is not essential for skeletal muscle glucose uptake during exercise, and the higher skeletal muscle glucose uptake during exercise in nNOSµ(-/-) mice may be due to compensatory increases in AMPK activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glicemia/metabolismo , Músculo Esquelético/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Condicionamento Físico Animal , Animais , Feminino , Glucose/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fosforilação
6.
Elife ; 42015 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-26496200

RESUMO

T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of adenosine monophosphate-activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN-AMPK metabolic signaling nexus essential for selectively promoting Tfh responses.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diferenciação Celular , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Camundongos , Deleção de Sequência , Ubiquitina-Proteína Ligases/genética
7.
Biochem Biophys Res Commun ; 463(4): 818-24, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26086096

RESUMO

RATIONALE: Cardiac metabolism is thought to be altered in insulin resistance and type 2 diabetes (T2D). Our understanding of the regulation of cardiac substrate metabolism and insulin sensitivity has largely been derived from ex vivo preparations which are not subject to the same metabolic regulation as in the intact heart in vivo. Studies are therefore required to examine in vivo cardiac glucose metabolism under physiologically relevant conditions. OBJECTIVE: To determine the temporal pattern of the development of cardiac insulin resistance and to compare with dynamic approaches to interrogate cardiac glucose and intermediary metabolism in vivo. METHODS AND RESULTS: Studies were conducted to determine the evolution of cardiac insulin resistance in C57Bl/6 mice fed a high-fat diet (HFD) for between 1 and 16 weeks. Dynamic in vivo cardiac glucose metabolism was determined following oral administration of [U-(13)C] glucose. Hearts were collected after 15 and 60 min and flux profiling was determined by measuring (13)C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Cardiac insulin resistance, determined by euglycemic-hyperinsulinemic clamp, was evident after 3 weeks of HFD. Despite the presence of insulin resistance, in vivo cardiac glucose metabolism following oral glucose administration was not compromised in HFD mice. This contrasts our recent findings in skeletal muscle, where TCA cycle activity was reduced in mice fed a HFD. Similar to our report in muscle, glucose derived pyruvate entry into the TCA cycle in the heart was almost exclusively via pyruvate dehydrogenase, with pyruvate carboxylase mediated anaplerosis being negligible after oral glucose administration. CONCLUSIONS: Under experimental conditions which closely mimic the postprandial state, the insulin resistant mouse heart retains the ability to stimulate glucose metabolism.


Assuntos
Dieta Hiperlipídica , Técnica Clamp de Glucose , Glucose/metabolismo , Hiperinsulinismo/metabolismo , Metabolômica , Miocárdio/metabolismo , Animais , Cromatografia Gasosa-Espectrometria de Massas , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Cell Metab ; 21(5): 718-30, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25955207

RESUMO

Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.


Assuntos
Cistina Difosfato/análogos & derivados , Diglicerídeos/metabolismo , Etanolaminas/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Biogênese de Organelas , Animais , Cistina Difosfato/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , RNA Nucleotidiltransferases/genética , RNA Nucleotidiltransferases/metabolismo
9.
PLoS One ; 10(5): e0128398, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26020641

RESUMO

One serious side effect of statin drugs is skeletal muscle myopathy. Although the mechanism(s) responsible for statin myopathy remains to be fully determined, an increase in muscle atrophy gene expression and changes in mitochondrial content and/or function have been proposed to play a role. In this study, we examined the relationship between statin-induced expression of muscle atrophy genes, regulators of mitochondrial biogenesis, and markers of mitochondrial content in slow- (ST) and fast-twitch (FT) rat skeletal muscles. Male Sprague Dawley rats were treated with simvastatin (60 or 80 mg·kg(-1)·day(-1)) or vehicle control via oral gavage for 14 days. In the absence of overt muscle damage, simvastatin treatment induced an increase in atrogin-1, MuRF1 and myostatin mRNA expression; however, these were not associated with changes in peroxisome proliferator gamma co-activator 1 alpha (PGC-1α) protein or markers of mitochondrial content. Simvastatin did, however, increase neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) and AMPK α-subunit protein expression, and tended to increase total NOS activity, in FT but not ST muscles. Furthermore, simvastatin induced a decrease in ß-hydroxyacyl CoA dehydrogenase (ß-HAD) activity only in FT muscles. These findings suggest that the statin-induced activation of muscle atrophy genes occurs independent of changes in PGC-1α protein and mitochondrial content. Moreover, muscle-specific increases in NOS expression and possibly NO production, and decreases in fatty acid oxidation, could contribute to the previously reported development of overt statin-induced muscle damage in FT muscles.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Mitocôndrias Musculares/metabolismo , Proteínas Musculares/biossíntese , Atrofia Muscular/metabolismo , Sinvastatina/farmacologia , Fatores de Transcrição/metabolismo , Animais , Masculino , Mitocôndrias Musculares/patologia , Atrofia Muscular/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Ratos Sprague-Dawley
10.
Cell Metab ; 21(3): 403-16, 2015 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-25738456

RESUMO

Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.


Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Interleucina-6/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiologia , Transdução de Sinais/fisiologia , Tecido Adiposo/fisiologia , Animais , Receptor gp130 de Citocina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Interleucina-6/metabolismo
11.
Biochim Biophys Acta ; 1851(2): 210-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25490466

RESUMO

Hepatic insulin resistance is a major risk factor for the development of type 2 diabetes and is associated with the accumulation of lipids, including diacylglycerol (DAG), triacylglycerols (TAG) and ceramide. There is evidence that enzymes involved in ceramide or sphingolipid metabolism may have a role in regulating concentrations of glycerolipids such as DAG and TAG. Here we have investigated the role of sphingosine kinase (SphK) in regulating hepatic lipid levels. We show that mice on a high-fat high-sucrose diet (HFHS) displayed glucose intolerance, elevated liver TAG and DAG, and a reduction in total hepatic SphK activity. Reduced SphK activity correlated with downregulation of SphK1, but not SphK2 expression, and was not associated with altered ceramide levels. The role of SphK1 was further investigated by overexpressing this isoform in the liver of mice in vivo. On a low-fat diet (LFD) mice overexpressing liver SphK1, displayed reduced hepatic TAG synthesis and total TAG levels, but with no change to DAG or ceramide. These mice also exhibited no change in gluconeogenesis, glycogenolysis or glucose tolerance. Similarly, overexpression of SphK1 had no effect on the pattern of endogenous glucose production determined during a glucose tolerance test. Under HFHS conditions, normalization of liver SphK activity to levels observed in LFD controls did not alter hepatic TAG concentrations. Furthermore, DAG, ceramide and glucose tolerance were also unaffected. In conclusion, our data suggest that SphK1 plays an important role in regulating TAG metabolism under LFD conditions.


Assuntos
Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Fígado/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese , Triglicerídeos/metabolismo , Animais , Ceramidas/metabolismo , Sacarose Alimentar/metabolismo , Glucose/metabolismo , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Fosfotransferases (Aceptor do Grupo Álcool)/genética , RNA Mensageiro/biossíntese , Fatores de Tempo , Regulação para Cima
12.
Mamm Genome ; 25(9-10): 522-38, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25074441

RESUMO

Obesity and type 2 diabetes lessen the quality of life of those afflicted and place considerable burden on the healthcare system. Furthermore, the detrimental impact of these pathologies is expected to persist or even worsen. Diabetes is characterized by impaired insulin action and glucose homeostasis. This has led to a rapid increase in the number of mouse models of metabolic disease being used in the basic sciences to assist in facilitating a greater understanding of the metabolic dysregulation associated with obesity and diabetes, the identification of therapeutic targets, and the discovery of effective treatments. This review briefly describes the most frequently utilized models of metabolic disease. A presentation of standard methods and technologies on the horizon for assessing metabolic phenotypes in mice, with particular emphasis on glucose handling and energy balance, is provided. The article also addresses issues related to study design, selection and execution of metabolic tests of glucose metabolism, the presentation of data, and interpretation of results.


Assuntos
Glucose/metabolismo , Homeostase , Animais , Estado de Consciência , Metabolismo Energético , Glucose/química , Resistência à Insulina/genética , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metaboloma , Metabolômica/métodos , Camundongos , Camundongos Transgênicos , Modelos Animais , Mutação , Fenótipo
13.
Diabetes ; 63(6): 1881-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24430435

RESUMO

Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.


Assuntos
Respiração Celular , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Resistência à Insulina , Mitocôndrias Musculares/metabolismo , Obesidade/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia , Western Blotting , Peso Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Metabolismo Energético , Ácidos Graxos/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/fisiopatologia , Oxirredução , Fosforilação Oxidativa , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Sirtuína 1/metabolismo
14.
Endocrinology ; 154(1): 65-76, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23183172

RESUMO

FTY720 is a sphingosine-1-phosphate analog that has been shown to inhibit ceramide synthesis in vitro. Because ceramide accumulation in muscle is associated with insulin resistance, we aimed to examine whether FTY720 would prevent muscle ceramide accumulation in high fat-fed mice and subsequently improve glucose homeostasis. Male C57Bl/6 mice were fed either a chow or high fat-diet (HFD) for 6 wk, after which they were treated with vehicle or FTY720 (5 mg/kg) daily for a further 6 wk. The ceramide content of muscle was examined and insulin action was assessed. Whereas the HFD increased muscle ceramide, this was prevented by FTY720 treatment. This was not associated with alterations in the expression of genes involved in sphingolipid metabolism. Interestingly, the effects of FTY720 on lipid metabolism were not limited to ceramide because FTY720 also prevented the HFD-induced increase in diacylglycerol and triacylglycerol in muscle. Furthermore, the increase in CD36 mRNA expression induced by fat feeding was prevented in muscle of FTY720-treated mice. This was associated with an attenuation of the HFD-induced increase in palmitate uptake and esterification. In addition, FTY720 improved glucose homeostasis as demonstrated by a reduction in plasma insulin, an improvement in whole-body glucose tolerance, an increase in insulin-stimulated glucose uptake, and Akt phosphorylation in muscle. In conclusion, FTY720 exerts beneficial effects on muscle lipid metabolism that prevent lipid accumulation and improve glucose tolerance in high fat-fed mice. Thus, FTY720 and other compounds that target sphingosine-1-phosphate signaling may have therapeutic potential in treating insulin resistance.


Assuntos
Ceramidas/metabolismo , Gorduras na Dieta/efeitos adversos , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Animais , Cloridrato de Fingolimode , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Esfingosina/uso terapêutico
15.
Cell ; 151(2): 414-26, 2012 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-23063129

RESUMO

Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca(2+)-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of "selective partial agonists," capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.


Assuntos
Tecido Adiposo Marrom/metabolismo , Glicólise , Proteínas Hedgehog/metabolismo , Células Musculares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Quinases Proteína-Quinases Ativadas por AMP , Adipócitos/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Cílios/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Camundongos , Neoplasias/metabolismo , Obesidade/metabolismo , Proteínas Quinases/metabolismo , Receptor Smoothened
16.
Diabetes ; 61(12): 3148-55, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22961081

RESUMO

The sphingolipids sphingosine-1-phosphate (S1P) and ceramide are important bioactive lipids with many cellular effects. Intracellular ceramide accumulation causes insulin resistance, but sphingosine kinase 1 (SphK1) prevents ceramide accumulation, in part, by promoting its metabolism into S1P. Despite this, the role of SphK1 in regulating insulin action has been largely overlooked. Transgenic (Tg) mice that overexpress SphK1 were fed a standard chow or high-fat diet (HFD) for 6 weeks before undergoing several metabolic analyses. SphK1 Tg mice fed an HFD displayed increased SphK activity in skeletal muscle, which was associated with an attenuated intramuscular ceramide accumulation compared with wild-type (WT) littermates. This was associated with a concomitant reduction in the phosphorylation of c-jun amino-terminal kinase, a serine threonine kinase associated with insulin resistance. Accordingly, skeletal muscle and whole-body insulin sensitivity were improved in SphK1 Tg, compared with WT mice, when fed an HFD. We have identified that the enzyme SphK1 is an important regulator of lipid partitioning and insulin action in skeletal muscle under conditions of increased lipid supply.


Assuntos
Ceramidas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Western Blotting , Resistência à Insulina/genética , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reação em Cadeia da Polimerase
17.
J Appl Physiol (1985) ; 113(8): 1173-83, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22653994

RESUMO

The objective of this study was to test the hypothesis that exercise-stimulated muscle glucose uptake (MGU) is augmented by increasing mitochondrial reactive oxygen species (mtROS) scavenging capacity. This hypothesis was tested in genetically altered mice fed chow or a high-fat (HF) diet that accelerates mtROS formation. Mice overexpressing SOD2 (sod2(Tg)), mitochondria-targeted catalase (mcat(Tg)), and combined SOD2 and mCAT (mtAO) were used to increase mtROS scavenging. mtROS was assessed by the H(2)O(2) emitting potential (JH(2)O(2)) in muscle fibers. sod2(Tg) did not decrease JH(2)O(2) in chow-fed mice, but decreased JH(2)O(2) in HF-fed mice. mcat(Tg) and mtAO decreased JH(2)O(2) in both chow- and HF-fed mice. In parallel, the ratio of reduced to oxidized glutathione (GSH/GSSG) was unaltered in sod2(Tg) in chow-fed mice, but was increased in HF-fed sod2(Tg) and both chow- and HF-fed mcat(Tg) and mtAO. Nitrotyrosine, a marker of NO-dependent, reactive nitrogen species (RNS)-induced nitrative stress, was decreased in both chow- and HF-fed sod2(Tg), mcat(Tg), and mtAO mice. This effect was not changed with exercise. Kg, an index of MGU was assessed using 2-[(14)C]-deoxyglucose during exercise. In chow-fed mice, sod2(Tg), mcat(Tg), and mtAO increased exercise Kg compared with wild types. Exercise Kg was also augmented in HF-fed sod2(Tg) and mcat(Tg) mice but unchanged in HF-fed mtAO mice. In conclusion, mtROS scavenging is a key regulator of exercise-mediated MGU and this regulation depends on nutritional state.


Assuntos
Antioxidantes/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Potenciais de Ação/fisiologia , Ração Animal , Animais , Transporte Biológico/fisiologia , Catalase/metabolismo , Dieta Hiperlipídica , Dissulfeto de Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/metabolismo , Óxido Nítrico/metabolismo , Condicionamento Físico Animal/fisiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
18.
Am J Physiol Endocrinol Metab ; 303(3): E301-7, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22550064

RESUMO

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.


Assuntos
Exercício Físico/fisiologia , Glucose/metabolismo , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Animais , Humanos , Modelos Biológicos , Contração Muscular/fisiologia , Músculo Esquelético/química , Óxido Nítrico Sintase/metabolismo , Transdução de Sinais/fisiologia
19.
Diabetes ; 60(11): 2720-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21885872

RESUMO

OBJECTIVE: Exercise is an effective intervention to treat fatty liver. However, the mechanism(s) that underlie exercise-induced reductions in fatty liver are unclear. Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver. RESEARCH DESIGN AND METHODS: C57BL/6 mice were fed high-fat diet (HFD) and assessed using magnetic resonance, biochemical, and histological techniques to establish a timeline for fatty liver development over 20 weeks. Glucagon receptor null (gcgr(-/-)) and wild-type (gcgr(+/+)) littermate mice were subsequently fed HFD to provoke moderate fatty liver and then performed either 10 or 6 weeks of running wheel or treadmill exercise, respectively. RESULTS: Exercise reverses progression of HFD-induced fatty liver in gcgr(+/+) mice. Remarkably, such changes are absent in gcgr(-/-) mice, thus confirming the hypothesis that exercise-stimulated hepatic glucagon receptor activation is critical to reduce HFD-induced fatty liver. CONCLUSIONS: These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.


Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/terapia , Glucagon/metabolismo , Fígado/metabolismo , Atividade Motora , Receptores de Glucagon/metabolismo , Animais , Peso Corporal , Gorduras na Dieta/efeitos adversos , Progressão da Doença , Fígado Gorduroso/patologia , Metabolismo dos Lipídeos , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucagon/genética , Transdução de Sinais
20.
Diabetes ; 60(2): 416-26, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21270253

RESUMO

OBJECTIVE: The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin α(2)ß(1) was tested. RESEARCH DESIGN AND METHODS: The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic clamps on integrin α(2)ß(1)-null (itga2(-/-)), integrin α(1)ß(1)-null (itga1(-/-)), and wild-type littermate mice fed chow or HF. Integrin α(2)ß(1) and integrin α(1)ß(1) signaling pathways have opposing actions. RESULTS: HF-fed mice had IR and increased muscle collagen (Col) III and ColIV protein; the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF-fed itga2(-/-) mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1(-/-) mice was unchanged. Insulin sensitivity in chow-fed itga1(-/-) and itga2(-/-) mice was not different from wild-type littermates. CONCLUSIONS: ECM collagen expansion is tightly associated with muscle IR. Studies with itga2(-/-) mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin α(2)ß(1) interaction.


Assuntos
Matriz Extracelular/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Integrina alfa2beta1/metabolismo , Músculo Esquelético/metabolismo , Análise de Variância , Animais , Western Blotting , Colágeno Tipo III/metabolismo , Colágeno Tipo V/metabolismo , Dieta , Matriz Extracelular/efeitos dos fármacos , Técnica Clamp de Glucose , Imuno-Histoquímica , Integrina alfa2beta1/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Purinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Citrato de Sildenafila , Sulfonas/farmacologia
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