TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Costa, Rafael Menezes da; Neves, Karla B; Mestriner, Fabíola; Louzada‐Júnior, Paulo; Bruder‐Nascimento, Thiago; Tostes, Rita C.

doi:10.1186/s12933-016-0443-0

Cited by 75 publications

(46 citation statements)

References 67 publications

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“…These findings were supported by many other independent studies in multiple experimental models over time (for example, see (da Costa et al, 2016) and a complete list at www.metaflammation.org). While less definitive human genetics associations in which TNF polymorphisms have been linked to obesity, diabetes and other aspects of metabolic syndrome, including polycystic ovary syndrome and sleep apnea also started to emerge (Huang et al, 2012a; Sookoian et al, 2005).…”

Section: Signaling Pathways Connecting Immunity and Glucose Metabolissupporting

confidence: 78%

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

2017

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Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

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Section: Signaling Pathways Connecting Immunity and Glucose Metabolissupporting

confidence: 78%

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

2017

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“…[37][38][39] The depletion of hepatic PTEN suppresses hyperglycemia. 40) Overexpression of PTP1B also inhibits tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1.…”

Section: Discussionmentioning

confidence: 99%

Role of Supplementary Selenium on the Induction of Insulin Resistance and Oxidative Stress in NSY Mice Fed a High Fat Diet

Murano

Ogino

Okuno

et al. 2018

Biological & Pharmaceutical Bulletin

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The role of supplementary selenium on the induction of insulin resistance and oxidative stress in a diabetic mouse model was investigated in NSY mice on a high fat diet (HFD) and administered seleno-L-methionine (SeMet)-containing water for 12 weeks. Significant increases in oral glucose tolerance-tested (OGTT), insulin tolerance-tested, and non-fasting blood glucose levels were observed in mice on a HFD, as well as the significant increases in OGTT and non-fasting plasma insulin levels. Mice on a HFD had decreased plasma adiponectin levels and increased free fatty acid (FFA) levels. Supplementary SeMet significantly augmented OGTT blood glucose levels in mice on a HFD and plasma FFA levels in mice on a normal diet. The mRNA levels of six selenoproteins were measured, and glutathione peroxidase (GPx) 1 and selenoprotein P (SelP) were selected as candidates that may be associated with insulin resistance or oxidative stress in the liver. Hepatic GPx1 expression was elevated in mice on a HFD and SeMet supplementation, and SelP expression increased in mice on a HFD. Histopathological observations in hepatic tissues showed hypertrophy of parenchymal cells and significant expression of 4-hydroxy-2-nonenal in mice on a HFD, indicating lipid accumulation and oxidative stress induction. Hepatic protein tyrosine phosphatase activity also increased by a HFD. These results suggest that hepatic lipid accumulation in NSY mice on a HFD promoted oxidative stress and hepatic SelP expression, and supplementary SeMet induced hepatic GPx1 expression.Key words selenium; diabetes; insulin resistance; glutathione peroxidase 1; selenoprotein P; oxidative stress Type 2 diabetes mellitus is a metabolic disease associated with genetic and lifestyle factors 1) caused by the decline in insulin potency in organs, such as liver, muscle, and adipose tissue, and/or reduced insulin secretion from pancreatic β-cells. 2)This disease leads to diabetic peripheral neuropathy, nephropathy, and retinopathy by raising the level of blood glucose, and eventually gangrene, renal failure, and blindness.3) These pathologies are linked on an individual level to obesity and overweight, 4) on a physiological level to insulin resistance, 5) and on a cellular level to oxidative stress. 6) Insulin-resistant diabetes is a state of declined glucose uptake in target tissue cells, which do not properly respond to insulin and do not have a functioning insulin transduction system. 7) Intracellular production of reactive oxygen species (ROS) and redox activation of protein tyrosine phosphatase (PTP) 1B are involved in the decline of insulin signal transduction phosphorylation [8][9][10] and dysfunction in pancreatic β-cells. 11,12) Selenium (Se) is an essential trace element and functions as a key component of critical enzymes for redox homeostasis and protection from oxidative stress, which include the glutathione peroxidase (GPx) family and selenoprotein P (SelP). 13,14) GPx1 is located in the cytosol to remove hydrogen peroxide (H 2 O 2 ), which is generated by intrac...

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“…The proposed mechanisms include impaired anti‐contractile function, perivascular inflammation via production of pro‐inflammatory cytokines and chemokines and the accumulation of macrophages, as well as dysregulation of adipocyte‐derived adipokines (Guzik et al, ; Ketonen et al, ; Fernández‐Alfonso et al, ; Sun et al, ). TNF‐α, which plays a critical role in the development of vascular dysfunction, insulin resistance, inflammation and atherosclerosis, is produced by the PVAT (Omar et al, ; Virdis et al, ; da Costa et al, ). TNF‐α also induces adipocyte dysfunction, leading to a vicious circle between adipocytes and macrophages, which may aggravate inflammatory changes in PVAT (Takaoka et al, ; Oriowo, ).…”

Section: Introductionmentioning

confidence: 99%

Increased mitochondrial ROS generation mediates the loss of the anti‐contractile effects of perivascular adipose tissue in high‐fat diet obese mice

Costa

Fais

Dechandt

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEObesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue. EXPERIMENTAL APPROACHC57Bl/6J and TNF-α receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O 2 .-) and H 2 O 2 were assayed in PVAT and aortic rings were used to assess vascular function. KEY RESULTSAortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O 2 .-, dismutation of mitochondria-derived H 2 O 2 , uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O 2 .-and H 2 O 2 were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O 2 consumption rates in PVAT from HFD-fed mice. TNF-α inhibition reduced H 2 O 2 levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-α receptors. Generation of H 2 O 2 was prevented in PVAT from TNF-α receptor deficient obese mice. CONCLUSION AND IMPLICATIONSTNF-α-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.

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TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Cited by 75 publications

References 67 publications

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Role of Supplementary Selenium on the Induction of Insulin Resistance and Oxidative Stress in NSY Mice Fed a High Fat Diet

Increased mitochondrial ROS generation mediates the loss of the anti‐contractile effects of perivascular adipose tissue in high‐fat diet obese mice

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