An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice

Reilly, Shannon M.; Chiang, Shian Huey; Decker, Stuart J.; Chang, Louise; Uhm, Maeran; Larsen, Martha J.; Rubin, John R.; Mowers, Jonathan; White, Nicole M.; Hochberg, Irit; Downes, Michael; Yu, Ruth T.; Liddle, Christopher; Evans, Ronald M.; Oh, Dayoung; Li, Pingping; Olefsky, Jerrold M.; Saltiel, Alan R.

doi:10.1038/nm.3082

Cited by 365 publications

(447 citation statements)

References 61 publications

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“…Previous findings in transgenic/knockout rodents have shown an inverse relationship between TEE and sensitivity for HFD-induced steatosis (32,35,40,43). Importantly, much like sedentary humans, we observed that REE of our caged animals represented the vast majority of TEE (Ͼ70%).…”

Section: Discussionsupporting

confidence: 67%

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

Morris¹,

Jackman

Johnson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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PS, Thyfault JP. Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 307: E355-E364, 2014. First published June 24, 2014; doi:10.1152/ajpendo.00093.2014.-Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein, we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high-fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measurements of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared with HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared with HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared with HCR, suggesting reduced whole body lipid utilization in the LCR. This was confirmed by the observed lower whole body dietary fatty acid oxidation in LCR compared with HCR. Furthermore, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared with HCR. We conclude that rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole body and hepatic mitochondrial lipid oxidation. fatty liver; energy intake; fitness; obesity; energy expenditure LOW AEROBIC CAPACITY OR FITNESS is a powerful predictor of cardiovascular and all-cause mortality independent of other risk factors, including smoking, obesity, previous cardiovascular disease, and diabetes (18,19). Importantly, improving fitness also significantly increases survival in previously low-fit individuals (19). Aerobic capacity is also an independent predictor for the development of the metabolic syndrome and type 2 diabetes (12, 34). Low aerobic capacity is also a powerful predictor of nonalcoholic fatty liver disease (NA-FLD) prevalence (2) and negatively impacts lifestyle-based treatments for NAFLD (16). However, the mechanism(s) linking low aerobic capacity to metabolic disease processes remains unknown. In particular, there are limited data documenting the whole body and liver-specific energy metabolism phenotypes that exist between groups of differing aerobic capacities and how these different phenotypes may modulate susceptibility for NAFLD.NAFLD represents a spectrum of disease initially characterized by steatosis that may progress to hepatic in...

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Section: Discussionsupporting

confidence: 67%

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

Morris¹,

Jackman

Johnson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…4A). Moreover, treatment with amlexanox, an inhibitor specific for IKKe and TBK1 (35), also potently reduced RelA Ser468p in ECV cells under similar conditions (Fig. 5D).…”

Section: Immunoblot (B) Nf-κb Fold Induction Was Determined By Lucifmentioning

confidence: 69%

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi’s sarcoma. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKε is critically required for kGPCR tumorigenesis and links kGPCR to NF-κB activation. Using kGPCR-induced tumor models, we found that IKKε expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKε abolished tumor formation. Moreover, kGPCR interacted with and activated IKKε. Activated IKKε promoted NF-κB subunit RelA (also known as p65) phosphorylation, which correlated with NF-κB activation and inflammatory cytokine expression. The robust expression of IKKε and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKε effectively abrogated NF-κB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKε in promoting NF-κB activation and tumorigenesis induced by a viral GPCR.

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“…IRF3 protein levels were also elevated 5.6-fold in the adipocyte fraction of the epididymal fat pad and kinases TBK1 and IKK-ε, resulting in IRF3 dimerization, nuclear translocation, and DNA binding (16,20). Interestingly, levels of TBK1 and IKK-ε are both elevated in the adipose tissue of obese mice, and inhibition of these kinases by genetic or pharmacological means improves systemic insulin sensitivity (21,22).…”

Section: Irf3 Expression Is Elevated In Adipocytes From Obese Mice Anmentioning

confidence: 99%

IRF3 promotes adipose inflammation and insulin resistance and represses browning

Kumari¹,

Wang²,

Lantier³

et al. 2016

Journal of Clinical Investigation

143

129

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An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice

Cited by 365 publications

References 61 publications

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

IRF3 promotes adipose inflammation and insulin resistance and represses browning

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