Abstract
Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.
Highlights
Obesity is characterized by an excessive adipose tissue expansion due to an increase in nutrients intake and insufficient energetic expenditure
The number of naive CD4+ and CD8+ T cells was increased in subcutaneous adipose tissue (SAT) and the amount of effector memory CD4+ and CD8+ T cells was decreased in visceral adipose tissue (VAT) (Vandanmagsar et al, 2011). These findings suggest a model whereby the NLRP3 inflammasome-dependent production of IL-1β and IL-18 by adipose tissue macrophages favors macrophage-T cell activation leading to a sustained inflammation of adipose tissue (Vandanmagsar et al, 2011)
The discovery that metabolic diseases are associated with a lowgrade inflammatory state has opened a new area of research to understand how inflammation develops and how it impact on metabolic pathways
Summary
Obesity is characterized by an excessive adipose tissue expansion due to an increase in nutrients intake and insufficient energetic expenditure. Some studies have reported that C3H/HeJ, 10ScN, or male TLR4−/− mice gained less weight on a high-fat diet than their respective controls (Tsukumo et al, 2007; Davis et al, 2008; Radin et al, 2008; Saberi et al, 2009; Orr et al, 2012) This phenotype could be related to a protection against diet-induced leptin or insulin resistance in the hypothalamus in the absence of a functional TLR4 signaling (Kleinridders et al, 2009; Milanski et al, 2009; Könner and Brüning, 2011). Other studies have described a higher feeding efficiency of the C3H/HeJ mice with increased adipose tissue mass and adipocyte hypertrophy (Poggi et al, 2007), an increase in body weight gain and
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