Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 09/2001; 293(5535):1673-7. DOI: 10.1126/science.1061620
Source: PubMed

ABSTRACT We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.

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    • "Salicylate, at concentrations below 1 mM (Hawley et al., 2012), works primarily by inhibiting IKK-β activity, preventing phosphorylation and cleavage of IκB, thereby allowing this protein to keep NF-κB sequestered in the cytosol to prevent inflammatory transcriptional activity (Kopp and Ghosh, 1994; Pierce et al., 1996). Most other NSAID, in contrast, directly inhibit cyclooxygenase activity (Tegeder et al., 2001) and do not necessarily induce the same metabolic effects as salicylate (Yuan et al., 2001). "
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    ABSTRACT: For dairy cattle, the first several weeks of lactation represent the highest-risk period in their lives after their own neonatal period. Although more than 50% of cows during this period are estimated to suffer from at least one subclinical disorder, the complicated admixture of normal adaptations to lactation, infectious challenges, and metabolic disorders has made it difficult to determine which physiological processes are adaptive and which are pathological during this time. Subacute inflammation, a condition that has been well documented in obesity, has been a subject of great interest among dairy cattle physiologists in the past decade. Many studies have now clearly shown that essentially all cows experience some degree of systemic inflammation in the several days after parturition. The magnitude and likely persistence of the inflammatory state varies widely among cows, and several studies have linked the degree of postpartum inflammation to increased disease risk and decreased whole-lactation milk production. In addition to these associations, enhancing postpartum inflammation with repeated subacute administration of cytokines has impaired productivity and markers of health, whereas targeted use of nonsteroidal anti-inflammatory drugs during this window of time has enhanced whole-lactation productivity in several studies. Despite these findings, many questions remain about postpartum inflammation, including which organs are key initiators of this state and what signaling molecules are responsible for systemic and tissue-specific inflammatory states. Continued in vivo work should help clarify the degree to which mild postpartum inflammation is adaptive and whether the targeted use of anti-inflammatory drugs or nutrients can improve the health and productivity of dairy cows. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
    Journal of Dairy Science 07/2015; DOI:10.3168/jds.2015-9683 · 2.57 Impact Factor
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    • "Heterozygous deletion of IKKβ protects mice from insulin resistance in diet-induced and genetic models of obesity (Yuan et al. 2001). Moreover, salicylate improved insulin signalling through IKKβ inhibition (Yuan et al. 2001). IKKβ was then explored further in different tissues using conditional knockout mice. "
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    ABSTRACT: Low-grade inflammation is an established pathological condition that contributes to the development of obesity, insulin resistance and type 2 diabetes. Metabolic inflammation is dependent on multiple signalling events. In an overnutrition state, canonical inflammatory pathways are induced by inflammatory cytokines and lipid species. They can also be triggered through inflammasome activation as well as through cellular stress provoked by the unfolded protein response at the endoplasmic reticulum as well as by reactive oxygen species. In this chapter, we summarize the current knowledge about signalling events within the cell and describe how they impact on metabolic inflammation and whole-body metabolism. We particularly highlight the interplay between different signalling pathways that link low-grade inflammation responses to the inactivation of the insulin receptor pathway, ultimately leading to insulin resistance, a hallmark of type 2 diabetes.
    Handbook of experimental pharmacology 04/2015; DOI:10.1007/164_2015_4
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    • "lating adipocyte differentiation and metabolism (Herová et al., 2014). Clinically, aspirin treatment diminishes hypertriglyceridemia in both obese rodents (Yuan et al., 2001) and patients with type 2 diabetes mellitus (Hundal et al., 2002). And, in a mice model of adiposity , it was demonstrated that aspirin reduces hypertriglyceridemia by lowering cholesterol, triglyceride or (and) even free fatty acid production (van Diepen et al., 2011; Manjula and Devi, 1993). "
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    ABSTRACT: Aspirin has been reported to regulate lipid metabolism. However, the mechanism underlying the regulation is not clear. We presently investigated aspirin's promotion of AMP-activated protein kinase (AMPK) pathway activation in human hepatoma HepG2 cells by examining AMPK expression, the promotion of AMPK activation. Then we investigated the influence of aspirin-promoted AMPK signaling on fatty acid oxidation in HepG2 cells. The results demonstrated that aspirin treatment did not regulate the expression of AMPK and its downstream target, Acetyl-Coenzyme A Carboxylase (ACC), but activated the AMPK signaling pathway by promoting the phosphorylation of AMPK and ACC. And, interestingly, the promotion by aspirin is dependent of cellular esterase, which catalyzes aspirin to salicylate. Moreover, the activated AMPK signaling promoted the fatty acid oxidation, by promoting expression of Carnitine palmitoyltransferase I (CPT1) and Medium-Chain Acyl-CoA Dehydrogenase (MCAD) in both mRNA and protein levels. Thus, we confirmed in this study that aspirin promoted lipid oxidation by upregulating the AMPK signaling pathway.
    The Journal of Toxicological Sciences 02/2015; 40(1):127-36. DOI:10.2131/jts.40.127 · 1.29 Impact Factor
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