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1.
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
2.
Cell Rep ; 27(8): 2385-2398.e3, 2019 May 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.

3.
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
4.
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
5.
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.

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