1. Introduction

Obesity has become a worldwide health problem because it is strongly associated with metabolic syndromes including type 2 diabetes mellitus (T2DM), atherosclerosis and ischemic heart diseases [1, 2]. Accumulating evidence indicates that chronic low-grade inflammation has a

© The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and eproduction in any medium, provided the original work is properly cited.

crucial role in the pathogenesis of obesity-associated metabolic dysfunction [3, 4]. The chronic inflammatory alternations are associated with dynamic changes in the composition and function of immune cells in various tissues such as adipose tissue, pancreatic islet, liver, muscle, and hypothalamus [5–7]. A large number of inflammatory immune cells infiltrate into adipose tissue during the course of obesity. M1-like macrophages, an inflammatory type of macrophage, accumulate in adipose tissue and are major sources of inflammatory mediators such as tumor necrosis factor (TNF)-α and IL-6 [8].

The connective fiber content of adipose tissue dramatically increases by the upregulation of collagen expression, which in turn elevates the overall rigidity of adipose tissue and finally leads to fibrosis. The deficiency of collagen 6, a key component of the extracellular matrix in adipose tissue, significantly improves the phenotypes of obese mice, including adipocyte death and adipose tissue inflammation [9]. This implies that alterations in the extracellular matrix in adipose tissue are linked to the development of inflammation. Thus, inflammation and fibrosis are important targets for the treatment of obesity.

An obese state results in an elevation of circulating levels of fatty acids (FAs) and, subsequently, an increase in inflammation of adipose tissue [10]. Adipose macrophages play critical roles in the immune responses through several FA-sensing mechanisms, such as pattern recognition receptors (PRRs). PRRs such as toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) quickly recognize pathogenic agents [11]. It is now becoming even more apparent that these PRRs are not only able to recognize microbial components but also mediate immune responses to endogenous molecules, including those arising in metabolic disorders, such as FAs. These endogenous molecules have been termed danger-associated molecular patterns (DAMPs) and have similar functions as microbial components to activate immune responses [12]. In the obese state, TLR4 may be activated by saturated free FAs, such as palmitic acid, derived from hypertrophied adipocytes as a DAMP and promote adipose tissue inflammation and insulin resistance [13–15]. Inflammasomes are multimeric protein complexes that are crucial for caspase-1, IL-1β, and IL-18 production [16]. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domaincontaining-3 (NLRP3) inflammasome also senses obesity-associated FAs and contributes to obesity-induced inflammation and insulin resistance [17, 18]. Moreover, IL-1β inhibits insulin signaling in the insulin-target organs, including adipose tissue, liver, and skeletal muscle, and also induces dysfunction and cell death of insulin-producing pancreatic β cells [19]. Macrophage-inducible C-type lectin (Mincle) recognizes not only cord factor, a mycobacterial glycolipid, but also SAP130 released from dead cells [20, 21]. Furthermore, Mincle is highly expressed in M1 macrophages in adipose tissue and involved in the induction of adipose tissue fibrosis and insulin resistance during obesity [22, 23].

Plant-derived natural products and their derivatives or synthetic mimics make up a considerable portion of current drugs. These products have played an important role in treating T2DM, especially in Asian countries. We previously reported that glycyrrhizin (GL) and isoliquiritigenin (ILG), components of Glycyrrhiza uralensis (G. uralensis), inhibit TLR4 signaling at the receptor level on the cell surface, resulting in inhibition of NF-κB and mitogen-activated protein kinases (MAPKs) activation [24]. Furthermore, ILG potently inhibits NLRP3 inflammasome activation independent of its inhibitory action on TLR4 [25]. Our in vivo study revealed that ILG attenuated high-fat diet (HFD)-induced adipose tissue inflammation and insulin resistance by inhibiting NLRP3 inflammasome activation in adipose tissue [25]. In addition to inflammation, we recently reported that ILG impacts fibrogenesis in adipose tissue by targeting TLR4 and Mincle activation in macrophages. On the basis of these findings, natural products derived from G. uralensis may serve as lead compounds for the development of new anti-T2DM drugs.

This review article highlights the recent discoveries of the anti-inflammatory and anti-fibrotic effects and mechanisms of action of G. uralensis components that target PRRs. We will also overview our findings that ILG targets activation of TLR4, NLRP3 inflammasome, and Mincle. We will discuss the roles of innate immunity and potential mechanisms by which it participates in obesity-associated inflammation and fibrosis.
