IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

Weissmann, Laís; Quaresma, Paula G.F.; Santos, Amilton dos; Matos, Manuel Arlindo Amador de; Pascoal, Vinícius D'Ávila Bitencourt; Zanotto, Tamires M.; Castro, Gisele; Guadagnini, Dioze; Silva, Joelcimar Martins da; Velloso, Lı́cio A.; Bittencourt, Jackson Cioni; Lopes-Cendes, Íscia; Saad, Mário José Abdalla; Prada, Patrícia O.

doi:10.2337/db13-1817

Cited by 46 publications

(50 citation statements)

References 38 publications

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“…Previous studies have implicated IKKε in the pathology of a wide array of diseases, including cancer, inflammatory, and metabolic diseases [4,8,18]. Many studies indicate a critical role of IKKε in the pathophysiology of inflammatory diseases; it has been reported that inflammation appeared to be reduced in IKKε KO mice [19,21], and our previous study indicated that deficiency of IKKε inhibits inflammation and induces cardiac protection [7].…”

Section: Discussionmentioning

confidence: 77%

“…Pathways. This study is an effort to glean mechanistic insights into the underlying cause of AAA pathology, considering the involvement of ERK1/2 signaling in AAA [12] and the published studies demonstrating that IKKε is required for the induction of proinflammatory cytokines [18] and ERK1/2 activation [19]. We further hypothesized that IKKε might participate in the development of AAA via activation of the ERK1/2 pathways.…”

Section: Ikkε Regulated Ang Ii-activated Erk1/2 Signalingmentioning

confidence: 99%

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IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Chai

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

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Section: Discussionmentioning

confidence: 77%

Section: Ikkε Regulated Ang Ii-activated Erk1/2 Signalingmentioning

confidence: 99%

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Chai

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Our data correlate with a recent study showing that intrahypothalamic inhibition of IKKɛ decreases TNF-alpha levels, improves insulin and leptin sensitivity, and decreases food intake. 98 The molecular binomial TBK1/IKKɛ seems to have more versatile functions related to the regulation of body glucose homeostasis. In a recent study, it was shown that inhibition of TBK1/IKKɛ in obese mice induces the release of IL-6, which stimulates phosphorylation of the Stat3 pathway in the liver, suppressing gluconeogenesis.…”

Section: The Tlr-ikkβ-nf-κb Pathway In the Development Of Type 2 Diabmentioning

confidence: 99%

Microglia activation due to obesity programs metabolic failure leading to type two diabetes

et al. 2017

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Obesity is an energy metabolism disorder that increases susceptibility to the development of metabolic diseases. Recently, it has been described that obese subjects have a phenotype of chronic inflammation in organs that are metabolically relevant for glucose homeostasis and energy. Altered expression of immune system molecules such as interleukins IL-1, IL-6, IL-18, tumor necrosis factor alpha (TNF-α), serum amyloid A (SAA), and plasminogen activator inhibitor-1 (PAI-1), among others, has been associated with the development of chronic inflammation in obesity. Chronic inflammation modulates the development of metabolic-related comorbidities like metabolic syndrome (insulin resistance, glucose tolerance, hypertension and hyperlipidemia). Recent evidence suggests that microglia activation in the central nervous system (CNS) is a priority in the deregulation of energy homeostasis and promotes increased glucose levels. This review will cover the most significant advances that explore the molecular signals during microglia activation and inflammatory stage in the brain in the context of obesity, and its influence on the development of metabolic syndrome and type two diabetes.

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“…IKKε knockout (KO) mice are protected from the diet induced obesity and insulin resistance. Inhibition of IKKε with either chemical means on small interfering RNA suggested a reduction in the inhibitory phosphorylation of IRS1Ser 307 and insulin resistance via IR/IRS-1/Akt and JAK2/STAT3 pathways [80]. …”

Section: Iκb Kinase (Ikk)mentioning

confidence: 99%

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

2016

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Obesity induced low-grade inflammation (metaflammation) impairs insulin receptor signaling (IRS). This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), inhibitor of NF-kB kinase complex beta (IKKβ), AMP activated protein kinase (AMPK), protein kinase C (PKC), Rho associated coiled-coil containing protein kinase (ROCK) and RNA-activated protein kinase (PKR), etc. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor (IR) and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in Type II Diabetes Mellitus (T2-DM). Identifying the specific protein kinases involved in obesity induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity induced T2-DM.

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IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

Cited by 46 publications

References 38 publications

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Microglia activation due to obesity programs metabolic failure leading to type two diabetes

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

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