Roles of Chemokines and Chemokine Receptors in Obesity-Associated Insulin Resistance and Nonalcoholic Fatty Liver Disease

Abstract

Abundant evidence has demonstrated that obesity is a state of low-grade chronic inflammation that triggers the release of lipids, aberrant adipokines, pro-inflammatory cytokines, and several chemokines from adipose tissue. This low-grade inflammation underlies the development of insulin resistance and associated metabolic comorbidities such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). During this development, adipose tissue macrophages accumulate through chemokine (C-C motif) receptor 2 and the ligand for this receptor, monocyte chemoattractant protein-1 (MCP-1), is considered to be pivotal for the development of insulin resistance. To date, the chemokine system is known to be comprised of approximately 40 chemokines and 20 chemokine receptors that belong to the seven-transmembrane G protein-coupled receptor family and, as a result, chemokines appear to exhibit a high degree of functional redundancy. Over the past two decades, the physiological and pathological properties of many of these chemokines and their receptors have been elucidated. The present review highlights chemokines and chemokine receptors as key contributing factors that link obesity to insulin resistance, T2DM, and NAFLD.

Keywords: Kupffer cells; adipose tissue macrophage; chemokines; inflammation; insulin resistance; macrophage polarization; nonalcoholic fatty liver disease; obesity.

Figure 1

CCR5 promotes obesity-induced inflammation and insulin resistance. In a lean state, M2 macrophages are the primary resident macrophages and maintain insulin sensitivity. On the other hand, over nutrition and/or a lack of exercise can cause adipocyte hypertrophy, which initiates the secretion of MCP-1 and leads to the recruitment of circulating monocytes to adipose tissues. Subsequently, CCR2⁺ macrophages accumulate and presumably maintain inflammation as M1 macrophages in obese adipose tissue. Similarly, CCR5⁺ adipose tissue macrophages (ATMs) infiltrate and promote the inflammatory response. Once these ATMs are present and active, they can maintain a vicious cycle involving ATM recruitment and the production of inflammatory cytokines such as TNF-α, IL-6, and IL-1β in conjunction with adipocytes and other infiltrated immune cells. These secreted pro-inflammatory cytokines subsequently cause insulin resistance in adipose tissue, the liver, and skeletal muscle via the activation of several kinases, including JNK and NF-κB/AP1. Therefore, CCR5, independently from and/or cooperatively with CCR2, plays a pivotal role in the induction and maintenance of obesity-induced inflammation and insulin resistance.

Figure 2

Pathomechanisms during the progression to NASH. The development of NASH is initiated by several different risk factors including a high-fat diet, physical inactivity, and genetic predispositions that often lead to obesity and insulin resistance. Exaggerated fat intake and obesity lead to hyperglycemia, hyperlipidemia, and the over expressions of adipocytokines and chemokines and further contribute to insulin resistance in adipose tissue and the liver. Insulin resistance results in hepatic triglyceride (TG) synthesis and the increased delivery of free fatty acids (FFAs) to the liver. Additionally, hepatic steatosis acts as a “first hit” that is followed by a “second hit” in which inflammatory mediators can cause NASH and even cirrhosis. An enhanced storage of TG provokes a series of harmful consequences related to hepatocytes, such as uncontrolled lipid peroxidation, oxidative stress, and endoplasmic reticulum (ER) stress, which can activate hepatic inflammatory pathways. In particular, the recruitment of macrophage/Kupffer cells and an M1-dominant phenotypic shift in macrophages in the liver play a key role in the pathological progression of NASH.

Figure 3

Beneficial effects of β-cryptoxanthin on the progression of NASH. β-Cryptoxanthin, an antioxidant carotenoid, inhibits the progression of NASH by attenuating lipid accumulation, lipid peroxidation, and insulin resistance. Furthermore, β-cryptoxanthin decreases numbers of M1 macrophages while increasing those of M2 macrophages, which results in an M2-dominant shift in Kupffer cells and leads to an attenuation of lipid-induced insulin resistance, inflammation, and fibrosis in NASH.