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1.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417460

RESUMO

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Restrição Calórica , Linhagem Celular , Colforsina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagon/metabolismo , Glucocorticoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicosilação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Ácido Pirúvico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
2.
Nat Commun ; 11(1): 5808, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199701

RESUMO

Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.


Assuntos
Biocatálise , Homeostase , Metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-vav/metabolismo , Transdução de Sinais , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Biocatálise/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Genótipo , Glucose/farmacologia , Homeostase/efeitos dos fármacos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo
3.
Diabetes ; 69(11): 2324-2339, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32778569

RESUMO

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can 1) promote the brown fat thermogenic program and fatty acid oxidation, 2) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, 3) change the gut microbiota composition, and 4) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.


Assuntos
Aminoácidos/administração & dosagem , Proteínas na Dieta/administração & dosagem , Metabolismo Energético/fisiologia , Homeostase , Obesidade/dietoterapia , Adipocinas/metabolismo , Ração Animal/análise , Animais , Composição Corporal , Dieta , Proteínas na Dieta/análise , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Longevidade , Camundongos , Camundongos Endogâmicos C57BL
4.
Swiss Med Wkly ; 150: w20273, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32564344

RESUMO

The discovery and administration of exogenous insulin has revolutionised diabetes treatment and continues, almost 100 years on, to be the basis for the management of insulin deficiency. However, insulin therapy still has potentially life-threatening side effects such as hypoglycaemia and increased risk of cardiovascular disease. So far, improvements in insulin therapy have focused mainly on modulating its pharmacokinetic and pharmacodynamic properties and improving delivery methods, while variations in the insulin sensitivity of peripheral tissues has received relatively little attention. Notably, tissue insulin sensitivity has been shown to vary considerably around the clock, which could contribute greatly to the effect (and risk of side effects) of a given dose of insulin. Recent evidence suggests that photic inputs regulate diurnal variations in the insulin sensitivity of metabolically relevant tissues via a previously unrecognised mechanism involving the ventromedial hypothalamic nucleus. Therefore, understanding the mechanisms underlying photic control of insulin action is of paramount medical importance. In addition, considering “when” (i.e., the time of day) could assist in deciding “how much” insulin should be administered and hence could aid the fine-tuning of insulin dosage, lowering the risk of side effects, and improving the quality of life of patients with insulin deficiency.

5.
Cell Rep ; 30(11): 3851-3863.e6, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187554

RESUMO

Cancer therapy is limited, in part, by lack of specificity. Thus, identifying molecules that are selectively expressed by, and relevant for, cancer cells is of paramount medical importance. Here, we show that peptidyl-prolyl-cis-trans-isomerase (PPIase) FK506-binding protein 10 (FKBP10)-positive cells are present in cancer lesions but absent in the healthy parenchyma of human lung. FKBP10 expression negatively correlates with survival of lung cancer patients, and its downregulation causes a dramatic diminution of lung tumor burden in mice. Mechanistically, our results from gain- and loss-of-function assays show that FKBP10 boosts cancer growth and stemness via its PPIase activity. Also, FKBP10 interacts with ribosomes, and its downregulation leads to reduction of translation elongation at the beginning of open reading frames (ORFs), particularly upon insertion of proline residues. Thus, our data unveil FKBP10 as a cancer-selective molecule with a key role in translational reprogramming, stem-like traits, and growth of lung cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Biossíntese de Proteínas , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Peptidilprolil Isomerase/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ribossomos/metabolismo
6.
Nat Commun ; 10(1): 3545, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391467

RESUMO

Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that S100A9, also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of S100A9 alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of S100A9. Thus, our data identify the S100A9/TLR4 axis as a putative target for ID care.


Assuntos
Calgranulina B/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo , Longevidade/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Toxina Diftérica/toxicidade , Ácidos Graxos/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Insulina/deficiência , Leptina/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Oxirredução , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estreptozocina/toxicidade , Receptor 4 Toll-Like/genética
7.
Cell Rep ; 27(8): 2385-2398.e3, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31116983

RESUMO

Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet the brain and peripheral pathways linking proper insulin effect to diurnal changes in light-dark and feeding-fasting inputs are poorly understood. Here, we show that the insulin sensitivity of several metabolically relevant tissues fluctuates during the 24 h period. For example, in mice, the insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function.


Assuntos
Insulina/metabolismo , Músculo Esquelético/metabolismo , Fototerapia/métodos , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Animais , Ritmo Circadiano , Humanos , Camundongos
8.
Cell Rep ; 26(2): 346-355.e3, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625317

RESUMO

Insulin action in the hypothalamus results in the suppression of hepatic glucose production (HGP). Obesity is often associated with a diminished response to insulin, leading to impaired suppression of HGP in obese mice. Here, we demonstrate that blocking central leptin signaling in diet-induced obese (DIO) mice restores the liver's ability to suppress glucose production. Leptin increases the expression of the insulin receptor phosphatase PTP1B, which is highly expressed in the hypothalamus of DIO mice. We demonstrate that the central pharmacological inhibition or ARH-targeted deletion of PTP1B restores the suppression of HGP in obese mice. Additionally, mice that lack PTP1B in AgRP neurons exhibit enhanced ARH insulin signaling and have improved glucose tolerance and insulin sensitivity. Overall, our findings indicate that obesity-induced increases in PTP1B diminish insulin action in the hypothalamus, resulting in unconstrained HGP and contributing to hyperglycemia in obesity.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Gluconeogênese , Insulina/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Transdução de Sinais
9.
Diabetes ; 67(11): 2213-2226, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30104247

RESUMO

AMPK is a cellular gauge that is activated under conditions of low energy, increasing energy production and reducing energy waste. Current evidence links hypothalamic AMPK with the central regulation of energy balance. However, it is unclear whether targeting hypothalamic AMPK has beneficial effects in obesity. Here, we show that genetic inhibition of AMPK in the ventromedial nucleus of the hypothalamus (VMH) protects against high-fat diet (HFD)-induced obesity by increasing brown adipose tissue (BAT) thermogenesis and subsequently energy expenditure. Notably, this effect depends upon the AMPKα1 isoform in steroidogenic factor 1 (SF1) neurons of the VMH, since mice bearing selective ablation of AMPKα1 in SF1 neurons display resistance to diet-induced obesity, increased BAT thermogenesis, browning of white adipose tissue, and improved glucose and lipid homeostasis. Overall, our findings point to hypothalamic AMPK in specific neuronal populations as a potential druggable target for the treatment of obesity and associated metabolic disorders.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Dieta Hiperlipídica/efeitos adversos , Neurônios/metabolismo , Obesidade/metabolismo , Fatores de Processamento de RNA/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Tecido Adiposo Marrom/metabolismo , Animais , Composição Corporal/fisiologia , Metabolismo Energético/fisiologia , Masculino , Obesidade/etiologia , Obesidade/genética , Consumo de Oxigênio/fisiologia , Ratos , Ratos Sprague-Dawley
10.
Nat Commun ; 8(1): 1820, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29180649

RESUMO

Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Obesidade/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Adulto , Idoso , Animais , Glicemia , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Células Hep G2 , Humanos , Inflamação/metabolismo , Insulina/sangue , Interleucina-6/metabolismo , Metabolismo dos Lipídeos , Lipopolissacarídeos/efeitos adversos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Modelos Animais , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/complicações , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/biossíntese , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Sirtuína 1/metabolismo
12.
Cell Rep ; 18(8): 1858-1868, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28228253

RESUMO

Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation.


Assuntos
Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/fisiologia , Transdução de Sinais/fisiologia , Transcrição Genética/fisiologia
13.
Cell Metab ; 23(3): 467-78, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26959185

RESUMO

Organismal homeostasis relies on coherent interactions among tissues, specifically between brain-driven functions and peripheral metabolic organs. Hypothalamic circuits compute metabolic information to optimize energetic resources, but the role of the circadian clock in these pathways remains unclear. We have generated mice with targeted ablation of the core-clock gene Bmal1 within Sf1-neurons of the ventromedial hypothalamus (VMH). While this mutation does not affect the central clock in the suprachiasmatic nucleus (SCN), the VMH clock controls cyclic thermogenesis in brown adipose tissue (BAT), a tissue that governs energy balance by dissipating chemical energy as heat. VMH-driven control is exerted through increased adrenergic signaling within the sympathetic nervous system, without affecting the BAT's endogenous clock. Moreover, we show that the VMH circadian clock computes light and feeding inputs to modulate basal energy expenditure. Thus, we reveal a previously unsuspected circuit where an SCN-independent, hypothalamic circadian clock controls BAT function, energy expenditure, and thermogenesis.


Assuntos
Metabolismo Energético , Núcleo Supraquiasmático/fisiologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Relógios Circadianos , Ritmo Circadiano , Homeostase , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Proteínas Circadianas Period/fisiologia , Sistema Nervoso Simpático/fisiologia , Termogênese
14.
Mol Metab ; 4(11): 846-56, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26629408

RESUMO

OBJECTIVE: Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM. METHODS: To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle. RESULTS: Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls. CONCLUSIONS: Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment.

15.
Front Neurosci ; 9: 108, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25870537

RESUMO

Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS) regulates glucose metabolism in an insulin-independent manner.

16.
Endocrinology ; 156(6): 2174-84, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25763637

RESUMO

Circadian rhythms govern homeostasis and organism physiology. Nutritional cues act as time givers, contributing to the synchronization between central and peripheral clocks. Neuronal food-synchronized clocks are thought to reside in hypothalamic nuclei such as the ventromedial hypothalamus (VMH) and the dorsomedial hypothalamus or extrahypothalamic brain areas such as nucleus accumbens. Interestingly, the metabolic sensor of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1) is highly expressed in the VMH and was shown to contribute to both control of energy balance and clock function. We used mice with targeted ablation of Sirt1 in the steroidogenic factor 1 neurons of the VMH to gain insight on the role played by this deacetylase in the modulation of the central clock by nutritional inputs. By studying circadian behavior and circadian gene expression, we reveal that SIRT1 operates as a metabolic sensor connecting food intake to circadian behavior. Indeed, under food restriction and absence of light, SIRT1 in the VMH contributes to activity behavior and circadian gene expression in the suprachiasmatic nucleus. Thus, under specific physiological conditions, SIRT1 contributes to the modulation of the circadian clock by nutrients.


Assuntos
Relógios Circadianos/fisiologia , Proteínas de Ligação a DNA/metabolismo , Neurônios/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Encéfalo/metabolismo , Relógios Circadianos/genética , Proteínas de Ligação a DNA/genética , Masculino , Camundongos , Fatores de Processamento de RNA , Sirtuína 1/genética , Fatores de Transcrição/genética
17.
Cell Metab ; 21(1): 117-25, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25533479

RESUMO

Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer.


Assuntos
Dieta , Neoplasias Pulmonares/patologia , Fenilbutiratos/toxicidade , Proteínas ras/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Regulação para Baixo , Doxiciclina/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos SCID , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a Tacrolimo/antagonistas & inibidores , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo , Transplante Heterólogo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteínas ras/genética
18.
Aging (Albany NY) ; 6(2): 92-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24589844

RESUMO

Diabetes afflicts hundreds of millions worldwide. People affected by type 1 diabetes mellitus (T1DM; the insulin-deficient form of diabetes) or type 2 diabetes mellitus (T2DM; the insulin-resistant form of diabetes) have significantly reduced life expectancy compared to normal individuals. This is due in part to the fact that (despite improvements) current anti-diabetic approaches are suboptimal. Indeed, severe morbidities (e.g.: cardiovascular disease, hypertension) are still too often associated with diabetes. Recent preclinical results indicate that different types of hypothalamic neurons are endowed with the ability to mediate the hyperglycemia-lowering action of the adipocyte-derived hormone leptin in an insulin-dependent and insulin-independent fashion. These results may pave the way for better anti-diabetic approaches and therefore positively impact on life expectancy of diabetic subjects.


Assuntos
Envelhecimento/metabolismo , Glucose/metabolismo , Hipotálamo/fisiologia , Insulina/fisiologia , Leptina/fisiologia , Animais , Diabetes Mellitus/terapia , Humanos
19.
Cell Metab ; 18(3): 431-44, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-24011077

RESUMO

The dogma that life without insulin is incompatible has recently been challenged by results showing the viability of insulin-deficient rodents undergoing leptin monotherapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin deficiency. Our analyses indicate that enhanced glucose uptake by brown adipose tissue and soleus muscle, as well as improved hepatic metabolism, underlies these effects of leptin. Collectively, our data elucidate a hypothalamic-dependent pathway enabling life without insulin and hence pave the way for developing better treatments for diseases of insulin deficiency.


Assuntos
Hipotálamo/efeitos dos fármacos , Insulina/metabolismo , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Glucose/análise , Hiperglicemia/tratamento farmacológico , Hiperglicemia/mortalidade , Hipotálamo/metabolismo , Estimativa de Kaplan-Meier , Leptina/uso terapêutico , Fígado/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Neurônios/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
20.
PLoS One ; 7(10): e48643, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23119079

RESUMO

Clinical research shows an association between polycystic ovary syndrome (PCOS) and chronic inflammation, a pathological state thought to contribute to insulin resistance. The underlying pathways, however, have not been defined. The purpose of this study was to characterize the inflammatory state of a novel mouse model of PCOS. Female mice lacking leptin and insulin receptors in pro-opiomelanocortin neurons (IR/LepR(POMC) mice) and littermate controls were evaluated for estrous cyclicity, ovarian and adipose tissue morphology, and body composition by QMR and CT scan. Tissue-specific macrophage infiltration and cytokine mRNA expression were measured, as well as circulating cytokine levels. Finally, glucose regulation during pregnancy was evaluated as a measure of risk for diabetes development. Forty-five percent of IR/LepR(POMC) mice showed reduced or absent ovulation. IR/LepR(POMC) mice also had increased fat mass and adipocyte hypertrophy. These traits accompanied elevations in macrophage accumulation and inflammatory cytokine production in perigonadal adipose tissue, liver, and ovary. These mice also exhibited gestational hyperglycemia as predicted. This report is the first to show the presence of inflammation in IR/LepR(POMC) mice, which develop a PCOS-like phenotype. Thus, IR/LepR(POMC) mice may serve as a new mouse model to clarify the involvement of adipose and liver tissue in the pathogenesis and etiology of PCOS, allowing more targeted research on the development of PCOS and potential therapeutic interventions.


Assuntos
Adipócitos/metabolismo , Modelos Animais de Doenças , Inflamação/genética , Síndrome do Ovário Policístico/genética , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Glicemia/metabolismo , Feminino , Expressão Gênica , Humanos , Hipertrofia , Inflamação/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Ovário/metabolismo , Ovário/patologia , Ovulação/genética , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Gravidez , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X
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