Review
Toll-like receptors: linking inflammation to metabolism

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Obesity has been characterized as a state of chronic inflammation. Inflammatory signaling not only causes peripheral insulin resistance, but also promotes neuronal insulin and leptin resistance, which further propagates a positive energy balance. Upon development of obesity, numerous conditions, including increased circulating cytokine concentrations and cell autonomous dysregulation of homeostatic signaling pathways, such as the endoplasmic reticulum stress response, promote activation of stress kinases, to cause peripheral insulin as well as central insulin and leptin resistance. Recently, activation of toll-like receptor (TLR) signaling has been recognized as an alternative activator of obesity-induced inflammation. In this paper, we review recent progress in defining the molecular basis of obesity-associated TLR activation and its role in the development of metabolic syndrome.

Section snippets

Obesity causes chronic low-grade inflammation

The worldwide prevalence of obesity has progressively increased over the past 30 years. The World Health Organization estimates that by 2015, approximately 700 million adults will be obese [1]. Cardiovascular disease, type 2 diabetes mellitus (T2DM), fatty liver disease and obesity related cancers are the main health problems accounting for the morbidity associated with the increasing prevalence of obesity [2].

The link between obesity, insulin resistance and T2DM has been recognized for

Etiology of obesity

Obesity is characterized by increased storage of FAs in an expanded adipose tissue mass, and by chronic activation of inflammatory pathways 7, 8. Survival of multicellular organisms ultimately depends on the ability to fight infection, and the capability of storing energy for times of low nutrient availability. Thus, nutrient and pathogen-sensing systems are highly conserved across species, from organisms such as Caenorhabditis elegans and Drosophila to mammals 4, 8.

Adipose tissue, apart from

Central regulation of energy homeostasis

Both energy intake and energy expenditure are, at least partly, under the tight control of defined neuronal circuits in the CNS that are targeted by leptin. These neural circuits also receive multiple inputs from peripheral organs to control food intake, energy expenditure and locomotor activity, and they also integrate a coordinated response that adapts metabolic processes such as regulation of hepatic gluconeogenesis, glucose disposal, insulin secretion and lipid partitioning, depending on

Obesity causes peripheral insulin resistance

The past decade has revealed important new insights into the role of innate immune response pathways in the development of obesity-associated peripheral insulin resistance. Obesity is characterized by a broad inflammatory response, and transcriptional profiling studies have revealed that inflammatory and stress response genes are among the most tightly regulated genes in the adipose tissue of obese animals [8].

The first indication for increased cytokine release in obesity was provided by the

Molecular mechanisms of insulin resistance

Inflammatory signaling cascades activated in obesity have been shown to be causally linked to the development of insulin resistance in peripheral tissues such as skeletal muscle and liver [8]. However, the interaction of inflammatory signaling and systemic insulin resistance is complex, as lack of IL-6 and IL-18, either in the whole body or specific tissues, also results in obesity and/or insulin resistance 41, 42, 43.

The molecular basis for the observed impairment in insulin action as a result

Role of FAs in insulin resistance

The consumption of fat-rich diets also contributes to the development of insulin resistance, T2DM and dyslipidemia [59]. As inflammatory signaling pathways contribute to these pathologies, intensive efforts have been made to identify potential mechanisms that might link the intake of dietary fat with inflammatory signaling. One proposed link has emerged from the finding that key molecular components of the innate immune system, TLRs, play a pivotal role in the development of insulin resistance

TLRs and innate immunity

TLRs are pattern-recognition receptors (PRRs) and play a crucial role in the innate immune system, which detects the presence and the nature of pathogenic microbial infection, and thus provides the first line of host defense (Box 1). TLRs, of which 12 members have been identified to date in mammals, comprise a family of type I transmembrane receptors, which are characterized by an extracellular leucine rich repeat (LRR) domain and an intracellular Toll/IL1 receptor (TIR) domain, which shows

TLR signaling induces peripheral insulin resistance

TLR4 is expressed in a variety of cell types, predominantly in the cells of the immune system, including macrophages and dendritic cells. TLR4 binds to the lipopolysaccharides (LPS) of Gram-negative bacterial cell walls [69]. Interestingly, the medium-chain FA component of LPS, lauric acid, is sufficient to trigger TLR4 signaling in a macrophage cell line 74, 75, 76. SFAs, circulating levels of which are often increased in obesity, thus represent important candidates for causing diet-induced

TLR signaling mediates central insulin and leptin resistance

In peripheral tissues, sustained exposure to a supply of nutrients exceeding energy requirements induces insulin resistance via multiple, convergent mechanisms [92]. Diverse tissues are affected by nutrient excess, so it is not surprising that the CNS, especially the hypothalamus, is also susceptible [93]. However, this carries the potential to cause obesity, rather than simply being its consequence, because insulin and leptin are crucial hormonal signals that inform the brain of the body's

Concluding remarks

The recognition that obesity is associated with chronic low-grade inflammation and that activation of inflammatory signaling contributes to the development of obesity-associated insulin resistance and T2DM has revolutionized our understanding of the pathophysiology of this common and socioeconomically important endocrine disorder. Although the identification of intracellular stress kinases such as JNK and IKK, which are activated upon obesity development, both in peripheral tissues and in the

Acknowledgements

We apologize to all colleagues whose important contributions could not be cited because of space limitations. We thank G. Schmall and T. Rayle for excellent secretarial assistance. This work was supported by the Center for Molecular Medicine (CMMC), University of Cologne (TVA1 to J.C.B.), the European Community's Seventh Framework Program (FP7/2007–2013) under grant agreement number 201608 (TOBI), the European Union (FP7-HEALTH-2009–241592, EurOCHIP, to J.C.B.), the DFG (BR 1492/7–1 to J.C.B.),

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