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Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009;138:961–975. (Reprinted with permission.)

Abstract

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Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-κB activation in mice, which leads to a sustained elevation in level of IκB kinase ε (IKKε) in liver, adipocytes, and adipose tissue macrophages. IKKε knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKε knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKε may represent an attractive therapeutic target for obesity, insulin resistance, diabetes, and other complications associated with these disorders.

Comment

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Visceral adiposity is associated with insulin resistance as well as hepatic steatosis and precedes the onset of nonalcoholic steatohepatitis (NASH) and type 2 diabetes.1 Overnutrition causes adipogenesis and proinflammatory signaling and may induce a state of low-grade chronic inflammation.2 This response is amplified by the subsequent recruitment of proinflammatory tissue macrophages to adipose depots through secretion of chemokines such as monocyte chemoattractant protein 1 and contributory factors like hypoxia and adipocyte hypertrophy.3, 4 Subsequently, these macrophages may be a major source of adipokines and proinflammatory cytokines that result in generation of the metabolic syndrome. Recent studies have suggested that white adipose tissue (WAT) is not merely a fat storage depot but may function as an endocrine organ capable of secreting adipokines like leptin, resistin, visfatin, plasminogen activator inhibitor 1, and inflammatory cytokines including interleukin-6 and tumor necrosis factor alpha (TNFα) which may then affect insulin signaling and inflammation in other tissues such as the liver, muscle and heart.5 Adipokines also act locally to block insulin signaling, resulting in lipolysis of triacylglycerols within adipocytes and adipose tissue macrophages, leading to release of free fatty acids (FFA) from WAT.6 Net influx of FFAs into the liver may overwhelm the capacity for fatty acid oxidation and lead to mitochondrial dysfunction, endoplasmic reticulum stress, and lipid peroxidation. Saturated FFAs induce innate immunity in the liver by binding toll-like receptors, a process which has been associated with the pathogenesis of NASH.7 Unsaturated fatty acids (specifically n6 polyunsaturated fatty acids), which are precursors of proinflammatory eicosinoids such as prostaglandins, leukotrienes, and thromboxanes, are strong mediators of inflammation.8 Thus influx of FFAs to the liver is thought to be a major contributing factor in the development of steatohepatitis in the obese.

There are two major pathways know to potentiate the effects of obesity on chronic inflammation and insulin signaling; the proinflammatory transcriptional regulatory nuclear factor kappa B (NF-κB) pathway and the serine/threonine phosphorylation c-Jun NH2-terminal kinase (JNK) pathway. Both activate proinflammatory responses, are regulated by pattern recognition receptors involved in innate immunity and act in opposition in TNFα-mediated programmed cell death. Blockade of either pathway results in protection from obesity-related insulin resistance in mice.9, 10 The NF-κB pathway is activated by Inhibitor of NF-κB (IκB) kinase β (IKKβ). IKKβ is part of a family of serine kinases that together form the IKK kinase complex. During basal conditions, inactive cytoplasmic NF-κB is complexed to IκB. Upon activation of this pathway, IKK phosphorylates IκB inducing its degradation, thus liberating NF-κB which is then translocated to the nucleus where it activates transcription of several target genes.

IKKβ has previously been shown to be a mediator of obesity-induced inflammation. The finding that salicylates, which have long been known to have antidiabetic properties, bind to IKKβ suggested a role for IKK.11 Subsequent work using rodent models of obesity-induced insulin resistance showed that either pharmacologic inhibition or genetic modification of IKKβ was associated with significant improvement in insulin sensitivity, reduction in circulating triglycerides and FFAs, and attenuation of hepatic steatosis and inflammation.12–14 The current study by Chiang et al.15 now demonstrates a new link between obesity and inflammation; the NF-κB-responsive IκB kinase ε (IKKε) was found to be elevated in adipocytes, liver and adipose tissue macrophages from obese mice fed a high-fat diet (HFD) which resulted in a state of chronic low-grade inflammation. Moreover, Chiang and colleagues showed that IKKε-deficient mice are protected from HFD-induced obesity and have improved glucose tolerance, hepatic and peripheral insulin sensitivity, and decreased expression of proinflammatory genes compared to wild-type (WT) counterparts. IKKε knockout mice are also protected from development of hepatic steatosis.

IKKε also appears to be important in viral immunity; in response to viral infection, IKKε induces interferon production via phosphorylation of the transcription factor interferon regulatory factor 3.16 Chiang et al., have now discovered an interesting new function for IKKε in the regulation of thermogenesis; IKKε knockout mice fed a HFD exhibited higher food intake per body weight, increased body temperature, and increased O2 consumption and energy expenditure without changes in carbohydrate or lipid metabolism, suggesting increased thermogenesis. Subsequent gene expression studies showed 10-fold increased expression of uncoupling protein 1 (UCP-1) in IKKε knockout mice on HFD. This finding suggests that IKKε may function to repress UCP-1 activation and regulate thermogenesis in response to dietary fat consumption by blocking UCP-1–mediated uncoupled oxidative phosphorylation during mitochondrial respiration. To investigate the role of IKKε in cellular metabolic processes such as lipogenesis, gluconeogenesis, and inflammation, the authors performed quantitative gene expression and microarray studies. Hepatic messenger RNA levels of the following genes were consistent with decreased lipid synthesis and export and improved insulin sensitivity in the liver of IKKε knockout mice, including reduced peroxisome proliferator-activated receptor gamma (PPARγ), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 4, and CD36, and increased PPARα, lipin1, and glucokinase. There was no significant difference in the IKKε knockout mice compared to WT mice in hepatic expression of genes involved in β-oxidation including Acox1, Acad1, carnitine palmitoyltransferase 1a, and medium chain acyl coenzyme A dehydrogenase. Serum levels and expression of adiponectin in WAT were reduced in HFD WT mice but were elevated in IKKε knockout mice, suggesting another potential mechanism for the improved hepatic and peripheral insulin sensitivity in these mice. A HFD produced significant increased expression of proinflammatory cytokines/chemokines including TNFα, Rantes, and macrophage inflammatory protein 1α both in liver and WAT in WT mice, which was not observed in the IKKε knockout mice. Decreased WAT expression of these genes was associated with a 90% reduction in adipose tissue macrophage infiltration in the IKKε knockout mice on HFD compared to controls. Lipopolysaccharide injection in IKKε–deficient mice resulted in IKKβ/IκB phosphorylation and cytokine production at a rate comparable to WT mice. These data suggest a role for IKKε in chronic obesity-related but not acute inflammation.

A limitation of this study is that it is difficult to distinguish the primary metabolic effects of IKKε deficiency from those that are the result of decreased adipose stores. For example, the increased thermogenesis in the IKKε knockout mice alone could explain the lean phenotype and associated decreased hepatic and circulating triglycerides, normalized glucose and insulin levels, and restored insulin signaling in WAT and liver. To address the role of IKKε in adipocyte insulin responsiveness directly, the authors transfected WT IKKε into cultured adipocytes and assayed for insulin-stimulated glucose uptake. Overexpression of IKKε in culture reduced insulin-stimulated glucose uptake by 50%, suggesting a direct cell autonomous effect of IKKε in promoting adipocyte insulin resistance. The authors then investigated the possibility that IKKε may be directly involved in transcriptional regulation through its function in kinase signaling. Expression of proinflammatory genes PPARγ, PDK4, Rantes, interferon-inducible protein 10, and inducible nitric oxide synthase were all increased in hepatoma cells following transfection of WT IKKε, but not a kinase-inactive mutant IKKε. This indicates IKKε functions to regulate hepatic inflammation and provides further evidence supporting a direct role for IKKε in the phenotype of the IKKε knockout mice independent of decreased obesity.

This study by Chiang and coworkers has important clinical implications but raises many additional questions. For instance, what are the cellular signals regulating IKKε, potentiating its role in inflammation, insulin resistance, and regulation of energy balance? Do the results of this study translate to humans and does increased activation of IKKε cause obesity in humans? Although it is intriguing to speculate that IKKε may emerge as an attractive therapeutic target for obesity and obesity-related diseases, the critical role of IKKε in viral immunity cannot be overlooked; IKKε knockout mice are prone to lethal viral infections.17 If the role of IKKε in inflammation and energy balance can be dissected from its function in innate immunity either by specific pharmacologic inhibitors or conditional/tissue-specific genetic modification, it is possible that IKKε may indeed represent an attractive therapeutic target for obesity.

References

  1. Top of page
  2. Abstract
  3. Comment
  4. References