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1.
Biochemistry ; 57(40): 5775-5779, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30226369

RESUMO

Methyl donor balance is critical for epigenetic regulation in cells and is maintained by the so-called methionine cycle proteins that regenerate S-adenosylmethionine (SAM), the universal methyl donor, from homocysteine formed by the activity of methyltransferases. Nnmt is a liver enzyme that methylates nicotinamide, but its role in regulating methyl donor balance in the liver is unclear. In this study, we assessed the effect of altered Nnmt expression on various aspects of methyl donor metabolism in the liver. We found that Nnmt overexpression decreased SAM levels and the SAM/ S-adenosylhomocysteine (SAH) ratio both in vivo and in vitro. Nnmt knockdown did not change methyl donor balance in mouse primary hepatocytes but increased SAM levels and the SAM/SAH ratio when Gnmt, the dominantly expressed methyltransferase in liver, was simultaneously knocked down. Paradoxically, expression of enzymatically deficient Nnmt increased the SAM/SAH ratio, suggesting that Nnmt can regulate methyl donor balance independent of its methyltransferase activity. Proteomics analysis of Nnmt-interacting proteins in the liver identified Bhmt, Mat1a, and Ahcy, all components of the methionine cycle, and functional experiments showed that mutant Nnmt increased the level of remethylation of homocysteine to SAM. In summary, we show that the function of Nnmt in hepatic methyl donor balance is multifactorial. On one hand, Nnmt decreases methyl donor balance, consistent with its activity as a methyltransferase consuming methyl donors. On the other hand, by co-opting the enzymes of the methionine cycle, Nnmt aids the recycling of homocysteine to SAM for another round of methylation.


Assuntos
Glicina N-Metiltransferase/metabolismo , Hepatócitos/enzimologia , Fígado/enzimologia , Nicotinamida N-Metiltransferase/metabolismo , S-Adenosilmetionina/metabolismo , Animais , Técnicas de Silenciamento de Genes , Glicina N-Metiltransferase/genética , Hepatócitos/citologia , Camundongos , Nicotinamida N-Metiltransferase/genética , S-Adenosil-Homocisteína/metabolismo
2.
FASEB J ; 31(10): 4482-4491, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28646016

RESUMO

Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-ß (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/ß administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.-Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Tireotropina Subunidade beta/genética , Tireotropina/metabolismo , Animais , Colesterol/metabolismo , Humanos , Hipotireoidismo/metabolismo , Camundongos
3.
Biochim Biophys Acta ; 1852(10 Pt A): 2056-65, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26170063

RESUMO

Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of ß-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice.

4.
Physiol Rep ; 12(18): e70058, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39324545

RESUMO

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity. Tie2 signaling is negatively regulated by the endothelial specific transmembrane receptor Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion of VEPTP protects from hypertension and diabetes induced renal injury in a mouse model of DKD. Here, we show that VEPTP inhibition with an extracellular domain targeting VEPTP antibody induced Tie2 phosphorylation and improved VEGF-A induced vascular permeability both in vitro and in vivo. Treatment with the VEPTP blocking antibody decreased the renal expression of endothelial activation markers (Angpt2, Edn1, and Icam1) but failed to improve kidney function in db/db uninephrectomized ReninAAV DKD mice.


Assuntos
Albuminúria , Nefropatias Diabéticas , Receptor TIE-2 , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Albuminúria/metabolismo , Camundongos , Receptor TIE-2/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/antagonistas & inibidores , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/antagonistas & inibidores , Masculino , Humanos , Camundongos Endogâmicos C57BL , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Modelos Animais de Doenças , Permeabilidade Capilar , Rim/metabolismo , Fosforilação , Células Endoteliais da Veia Umbilical Humana/metabolismo
5.
Drug Metab Dispos ; 41(3): 550-3, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23418369

RESUMO

Excess nicotinamide, a form of vitamin B(3), is metabolized through two enzymatic systems and eventually excreted from the body. The first system starts with the methylation of nicotinamide by nicotinamide N-methyltransferase, which can subsequently be oxidized by aldehyde oxidase. The second enzymatic system oxidizes nicotinamide to nicotinamide N-oxide. It is located in the endoplasmic reticulum of hepatocytes but the precise enzyme is unknown. We have used human liver microsomes in combination with selective cytochrome P450 inhibitors, specific substrates, and antibodies to identify CYP2E1 as the main activity producing nicotinamide N-oxide. Our results suggest the potential use of nicotinamide N-oxide as a biomarker of CYP2E1 activity from urine or blood samples.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Niacinamida/metabolismo , Complexo Vitamínico B/metabolismo , Biotransformação , Catálise , Inibidores do Citocromo P-450 CYP2E1 , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Niacinamida/análogos & derivados , Oxirredução , Especificidade por Substrato
6.
Cell Metab ; 6(5): 345-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17983579

RESUMO

Serotonergic agents have been used in the past for reduction of appetite and body weight. As reported by Zhou et al. (2007) in this issue of Cell Metabolism, they also have unexpected effects on peripheral glucose homeostasis independent of food intake and body weight.


Assuntos
Glucose/metabolismo , Homeostase/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Animais , Camundongos , Modelos Biológicos , Agonistas do Receptor 5-HT2 de Serotonina , Transdução de Sinais/efeitos dos fármacos
7.
Cell Metab ; 5(2): 115-28, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17276354

RESUMO

In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBPbeta and upstream of PPARgamma, in the cascade of factors that control adipogenesis, and it regulates PPARgamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPARgamma activity while constitutive overexpression increases activity of the PPARgamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPARgamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia.


Assuntos
Adipogenia , PPAR gama/genética , PPAR gama/metabolismo , Xantina Desidrogenase/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/enzimologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/enzimologia , Adiposidade/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Tamanho do Órgão/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologia , Xantina Desidrogenase/deficiência , Xantina Desidrogenase/genética
8.
Neuron ; 51(6): 811-22, 2006 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-16982425

RESUMO

Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-and-activator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.


Assuntos
Dopamina/metabolismo , Leptina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Anfetamina/farmacologia , Análise de Variância , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Sinergismo Farmacológico , Imuno-Histoquímica/métodos , Leptina/administração & dosagem , Leptina/genética , Camundongos , Camundongos Knockout , Camundongos Obesos , Microscopia Confocal , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores para Leptina , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
9.
Endocr Rev ; 27(6): 606-20, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16788162

RESUMO

Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified as a 17-amino-acid circulating hormone in teleost fish, where it is secreted by the pituitary in response to stress and environmental stimuli. In fish, MCH lightens skin color by stimulating aggregation of melanosomes, pigment-containing granules in melanophores, cells of neuroectodermal origin found in fish scales. Although the peptide structure between fish and mammals is highly conserved, in mammals, MCH has no demonstrable effects on pigmentation; instead, based on a series of pharmacological and genetic experiments, MCH has emerged as a critical hypothalamic regulator of energy homeostasis, having effects on both feeding behavior and energy expenditure.


Assuntos
Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Hormônios Hipotalâmicos/fisiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Sequência de Aminoácidos , Animais , Homeostase/fisiologia , Humanos , Hormônios Hipotalâmicos/química , Melaninas/química , Dados de Sequência Molecular , Hormônios Hipofisários/química
10.
Am J Physiol Endocrinol Metab ; 297(5): E1197-204, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19738035

RESUMO

In mice of normal weight and with diet-induced obesity, a high-fat, low-carbohydrate ketogenic diet (KD) causes weight loss, reduced circulating glucose and lipids, and dramatic changes in hepatic gene expression. Many of the effects of KD are mediated by fibroblast growth factor 21 (FGF21). We tested the effects of KD feeding on ob/ob mice to determine if metabolic effects would occur in obesity secondarily to leptin deficiency. We evaluated the effect of prolonged KD feeding on weight, energy homeostasis, circulating metabolites, glucose homeostasis, and gene expression. Subsequently, we evaluated the effects of leptin and fasting on FGF21 expression in ob/ob mice. KD feeding of ob/ob mice normalized fasting glycemia and substantially reduced insulin and lipid levels in the absence of weight loss. KD feeding was associated with significant increases in lipid oxidative genes and reduced expression of lipid synthetic genes, including stearoyl-coenzyme A desaturase 1, but no change in expression of inflammatory markers. In chow-fed ob/ob mice, FGF21 mRNA was elevated 10-fold compared with wild-type animals, and no increase from this elevated baseline was seen with KD feeding. Administration of leptin to chow-fed ob/ob mice led to a 24-fold induction of FGF21. Fasting also induced hepatic FGF21 in ob/ob mice. Thus, KD feeding improved ob/ob mouse glucose homeostasis without weight loss or altered caloric intake. These data demonstrate that manipulation of dietary macronutrient composition can lead to marked improvements in metabolic profile of leptin-deficient obese mice in the absence of weight loss.


Assuntos
Dieta com Restrição de Carboidratos , Dieta Cetogênica , Intolerância à Glucose/dietoterapia , Redução de Peso/fisiologia , Animais , Calorimetria Indireta , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/genética , Teste de Tolerância a Glucose , Homeostase/fisiologia , Mediadores da Inflamação/metabolismo , Resistência à Insulina/fisiologia , Interleucina-6/metabolismo , Leptina/sangue , Leptina/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/dietoterapia , RNA/biossíntese , RNA/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Mol Metab ; 29: 114-123, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31668382

RESUMO

OBJECTIVE: Melanin-concentrating hormone (MCH) plays a key role in regulating energy balance. MCH acts via its receptor MCHR1, and MCHR1 deletion increases energy expenditure and locomotor activity, which is associated with a hyperdopaminergic state. Since MCHR1 expression is widespread, the neurons supporting the effects of MCH on energy expenditure are not clearly defined. There is a high density of MCHR1 neurons in the striatum, and these neurons are known to be GABAergic. We thus determined if MCH acts via this GABAergic neurocircuit to mediate energy balance. METHODS: We generated a Mchr1-flox mouse and crossed it with the Vgat-cre mouse to assess if MCHR1 deletion from GABAergic neurons expressing the vesicular GABA transporter (vGAT) in female Vgat-Mchr1-KO mice resulted in lower body weights or increased energy expenditure. Additionally, we determined if MCHR1-expressing neurons within the accumbens form part of the neural circuit underlying MCH-mediated energy balance by delivering an adeno-associated virus expressing Cre recombinase to the accumbens nucleus of Mchr1-flox mice. To evaluate if a dysregulated dopaminergic tone leads to their hyperactivity, we determined if the dopamine reuptake blocker GBR12909 prolonged the drug-induced locomotor activity in Vgat-Mchr1-KO mice. Furthermore, we also performed amperometry recordings to test whether MCHR1 deletion increases dopamine output within the accumbens and whether MCH can suppress dopamine release. RESULTS: Vgat-Mchr1-KO mice have lower body weight, increased energy expenditure, and increased locomotor activity. Similarly, restricting MCHR1 deletion to the accumbens nucleus also increased locomotor activity. Vgat-Mchr1-KO mice show increased and prolonged sensitivity to GBR12909-induced locomotor activity, and amperometry recordings revealed that GBR12909 elevated accumbens dopamine levels to twice that of controls, thus MCHR1 deletion may lead to a hyperdopaminergic state that mediates their observed hyperactivity. Consistent with the inhibitory effect of MCH, we found that MCH acutely suppresses dopamine release within the accumbens. CONCLUSIONS: As with established models of systemic MCH or MCHR1 deletion, we found that MCHR1 deletion from GABAergic neurons, specifically those within the accumbens nucleus, also led to increased locomotor activity. A hyperdopaminergic state underlies this increased locomotor activity, and is consistent with our finding that MCH signaling within the accumbens nucleus suppresses dopamine release. In effect, MCHR1 deletion may disinhibit dopamine release leading to the observed hyperactivity.


Assuntos
Neurônios GABAérgicos/metabolismo , Locomoção , Receptores de Somatostatina/metabolismo , Animais , Dopamina/metabolismo , Metabolismo Energético , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Núcleo Accumbens/metabolismo , Piperazinas/farmacologia , Receptores de Somatostatina/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/deficiência , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética
12.
Diabetes ; 56(2): 311-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17259374

RESUMO

Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal beta-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in beta-cell mass and complemented our earlier observation of increased beta-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent beta-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4alpha, and HNF1alpha. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of beta-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis.


Assuntos
Gorduras na Dieta/farmacologia , Células Secretoras de Glucagon/metabolismo , Hormônios Hipotalâmicos/metabolismo , Células Secretoras de Insulina/metabolismo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Expressão Gênica , Humanos , Hormônios Hipotalâmicos/genética , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Melaninas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hormônios Hipofisários/genética , Transdução de Sinais/fisiologia
13.
Mol Nutr Food Res ; 62(14): e1700933, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29688621

RESUMO

SCOPE: The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue. We hypothesized an epigenetic signature in association with NNMT gene expression in adipose tissue. METHODS AND RESULTS: The global human methylome was analyzed in visceral adipose tissue (VAT) from morbidly obese patients using the Infinium Human Methylation 450 BeadChip array (discovery cohort: n = 11). The findings were confirmed in two additional independent cohorts (cohort 1: n = 60; BMI 20-60 kg m-2 and cohort 2: n = 40; BMI > 40 kg m-2 ) and validated after weight loss (using microarray data). Among the genes associated with the largest methylation fold change were genes related to metabolic processes, proliferation, inflammation, and extracellular matrix remodeling, such as COL23A1, PLEC1, FBXO21, STEAP3, RGS12, IGDCC3, FOXK2, and ORAI2. In fact, the results showed 577 differentially methylated CpG sites (DMCpGs) associated with the NNMT expression levels, with low methylation levels paralleling high NNMT expression. The expression of FBXO21 and FOXK2 was specifically modified after weight loss concomitantly with a decrease in NNMT expression and inflammation-related genes. Interestingly, the adipose tissue NNMT gene expression correlated with markers of adipose tissue inflammation. CONCLUSIONS: The expression of NNMT in VAT is associated with a specific methylome signature involving genes linked to adipose tissue metabolic pathophysiology.

14.
Diabetes ; 55(2): 428-34, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16443777

RESUMO

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH(-/-) mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH(-/-) model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH(-/-) mice up to 19 months. The lean phenotype of MCH(-/-) mice persisted over the duration of the study. At 19 months, MCH(-/-) male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH(-/-) mice. Aged MCH(-/-) mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH(-/-) mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH(-/-) mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.


Assuntos
Envelhecimento/fisiologia , Deleção de Genes , Hormônios Hipotalâmicos/deficiência , Hormônios Hipotalâmicos/metabolismo , Resistência à Insulina/genética , Melaninas/deficiência , Melaninas/metabolismo , Hormônios Hipofisários/deficiência , Hormônios Hipofisários/metabolismo , Aumento de Peso/genética , Envelhecimento/genética , Animais , Metabolismo Energético , Feminino , Hormônios Hipotalâmicos/genética , Masculino , Melaninas/genética , Camundongos , Atividade Motora , Fenótipo , Hormônios Hipofisários/genética , Proteína Supressora de Tumor p53/metabolismo
15.
Trends Endocrinol Metab ; 28(5): 340-353, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28291578

RESUMO

Nicotinamide (NAM) N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of NAM, one of the forms of vitamin B3. Methylated NAM is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as adipose and liver as well as cancer cells through the consumption of methyl donors and generation of active metabolites. This review examines recent findings regarding the function of NNMT in physiology and disease and highlights potential new avenues for therapeutic intervention. Finally, key gaps in our knowledge about this enzymatic system and future areas of investigation are discussed.


Assuntos
Niacinamida/metabolismo , Nicotinamida N-Metiltransferase/metabolismo , Tecido Adiposo/enzimologia , Tecido Adiposo/metabolismo , Animais , Humanos , Fígado/enzimologia , Fígado/metabolismo , Modelos Teóricos , Niacinamida/genética , Nicotinamida N-Metiltransferase/genética
16.
Cell Metab ; 25(2): 386-399, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28178568

RESUMO

While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-ß (Actß), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is upregulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control.


Assuntos
Ativinas/metabolismo , Drosophila melanogaster/metabolismo , Corpo Adiposo/metabolismo , Trato Gastrointestinal/metabolismo , Glucagon/metabolismo , Hiperglicemia/metabolismo , Receptores de Ativinas/metabolismo , Animais , Metabolismo dos Carboidratos , Proteínas de Transporte/metabolismo , Carboidratos da Dieta/efeitos adversos , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Células Enteroendócrinas/metabolismo , Hepatócitos/metabolismo , Hiperglicemia/patologia , Hormônios de Inseto/metabolismo , Larva/metabolismo , Camundongos , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Transdução de Sinais
17.
Hepatol Commun ; 1(8): 803-815, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29404495

RESUMO

Iron overload causes the generation of reactive oxygen species that can lead to lasting damage to the liver and other organs. The goal of this study was to identify genes that modify the toxicity of iron overload. We studied the effect of iron overload on the hepatic transcriptional and metabolomic profile in mouse models using a dietary model of iron overload and a genetic model, the hemojuvelin knockout mouse. We then evaluated the correlation of nicotinamide N-methyltransferase (NNMT) expression with body iron stores in human patients and the effect of NNMT knockdown on gene expression and viability in primary mouse hepatocytes. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism and that NNMT, an enzyme that methylates nicotinamide and regulates hepatic glucose and cholesterol metabolism, is one of the most strongly down-regulated genes in the liver in both genetic and dietary iron overload. We found that hepatic NNMT expression is inversely correlated with serum ferritin levels and serum transferrin saturation in patients who are obese, suggesting that body iron stores regulate human liver NNMT expression. Furthermore, we demonstrated that adenoviral knockdown of NNMT in primary mouse hepatocytes exacerbates iron-induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of NNMT partially reversed these effects. Conclusion: Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases NNMT expression, while NNMT deficiency worsens the toxic effect of iron overload. For these reasons, NNMT may be a drug target for the prevention of iron-induced hepatotoxicity. (Hepatology Communications 2017;1:803-815).

18.
Cell Metab ; 25(6): 1320-1333.e5, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28591635

RESUMO

Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/metabolismo , Animais , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Dextrotireoxina/metabolismo , Feminino , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Knockout
19.
Mol Metab ; 5(8): 690-698, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27656406

RESUMO

OBJECTIVE: Reproduction is an energetically expensive process. Insufficient calorie reserves, signaled to the brain through peripheral signals such as leptin, suppress fertility. Recently, fibroblast growth factor 21 (FGF21) was implicated as a signal from the liver to the hypothalamus that directly inhibits the hypothalamic-gonadotropin axis during fasting and starvation. However, FGF21 itself increases metabolic rate and can induce weight loss, which suggests that the effects of FGF21 on fertility may not be direct and may reflect changes in energy balance. METHODS: To address this important question, we evaluated fertility in several mouse models with elevated FGF21 levels including ketogenic diet fed mice, fasted mice, mice treated with exogenous FGF21 and transgenic mice over-expressing FGF21. RESULTS: We find that ketogenic diet fed mice remain fertile despite significant elevation in serum FGF21 levels. Absence of FGF21 does not alter transient infertility induced by fasting. Centrally infused FGF21 does not suppress fertility despite its efficacy in inducing browning of inguinal white adipose tissue. Furthermore, a high fat diet (HFD) can restore fertility of female FGF21-overexpressing mice, a model of growth restriction, even in the presence of supraphysiological serum FGF21 levels. CONCLUSIONS: We conclude that FGF21 is not a direct physiological regulator of fertility in mice. The infertility observed in FGF21 overexpressing mice is likely driven by the increased energy expenditure and consequent excess calorie requirements resulting from high FGF21 levels.

20.
Trends Endocrinol Metab ; 14(5): 243-8, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12826331

RESUMO

In recent years, the key role of melanin-concentrating hormone (MCH) in regulating mammalian energy balance has been confirmed through several lines of evidence. When administered exogenously, MCH leads to a rapid and robust feeding response and chronic infusions result in the development of mild obesity. At the physiological level, it is known that MCH expression changes in states of altered energy balance, such as fasting and obesity. Genetic studies with mice have shown that ablation of either the gene for prepro-MCH or the gene encoding the MCH receptor leads to a lean phenotype. Finally, the administration of MCH antagonists appears to inhibit both feeding and the development of diet-induced obesity. The aim of this article is to review the recent data on MCH and MCH receptors in light of their emerging roles in energy homeostasis.


Assuntos
Peixes/fisiologia , Hormônios Hipotalâmicos/fisiologia , Mamíferos/fisiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Fenômenos Fisiológicos da Pele , Sequência de Aminoácidos , Animais , Humanos , Hormônios Hipotalâmicos/biossíntese , Melaninas/biossíntese , Dados de Sequência Molecular , Hormônios Hipofisários/biossíntese , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/fisiologia
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