Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ
Harvard University, Cambridge, Massachusetts, United StatesScience (Impact Factor: 33.61). 09/2001; 293(5535):1673-7. DOI: 10.1126/science.1061620
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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- "Systemic glucose tolerance and insulin sensitivity were enhanced in HFD-fed FASKOF mice (notable for less adiposity) compared to controls (Figures 2B and 2C), but with chow feeding (a condition associated with similar degrees of adiposity in each genotype) there was no difference in glucose tolerance between FASKOF and control mice (Figure S1F). Consistent with the observation that decreased adiposity improves insulin sensitivity in numerous animal models (Elchebly et al., 1999; Masuzaki et al., 2001; Yang et al., 2005; Yuan et al., 2001), levels of phospho-Akt relative to total Akt were increased in skeletal muscle of HFD-fed FASKOF mice (data not shown). Serum leptin was lower (perhaps reflecting decreased adiposity) but adiponectin was unaffected in HFDfed FASKOF mice (Table S1). "
ABSTRACT: Nicotinamide (NAM) is the amide of nicotinic acid and a predominant precursor for NAD+ biosynthesis via the salvage pathway. Sirt1 is a NAD+-dependent deacetylase, playing an important role in regulating cellular functions. Although hepatoprotective effect of NAM has been reported, the underlying mechanism remains elusive. ER stress, induced by saturated fatty acids, in specific palmitate, plays a pathological role in the development of nonalcoholic fatty liver disease. This study aims to determine the effect of NAM on palmitate-induced ER stress in hepatocytes and to elucidatemolecularmechanismsbehind. Both HepG2 cells and primarymouse hepatocytes were exposed to palmitate (conjugated to BSA at a 2:1 M ratio), NAM, or their combination for different durations. Cellular NAD+ level, Sirt1 expression/activity, ER stress, as well as cAMP/PKA/CREB pathway activation were determined. NAMincreased Sirt1 expression and enzymatic activity, which contributes to the ameliorative effect of NAMon palmitate-triggered ER stress. NAMincreased intracellular NAD+ level in hepatocytes, however, blocking the salvage pathway, a pathway for NAD+ synthesis from NAM, only partially prevented NAM-induced Sirt1 upregulation while completely prevented NAD+ increase in response to NAM. Further mechanistic investigations revealed that NAMelevated intracellular cAMP level via suppressing PDE activity, leading to downstream PKA and CREB activation. Importantly, cAMP/PKA/CREB pathway blockade abolished not only NAM-induced Sirt1 upregulation, but also its protective effect against ER stress. Our results demonstrate that NAM protects hepatocytes against palmitate-induced ER stress in hepatocytes via upregulating Sirt1. Activation of the cAMP/PKA/ CREB pathway plays a key role in NAM-induced Sirt1 upregulation.Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 09/2015; 1853(11). DOI:10.1016/j.bbamcr.2015.09.003 · 5.02 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. "
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). "
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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