Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease

Abstract

Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.

Figure 1.

Concept of metabolic syndrome.

Figure 2.

Secretion of inflammatory adipokines from adipose tissue in obese state. In obese state, the enlarged adipose tissue leads to dysregulated secretion of adipokines and increased release of free fatty acids. The free fatty acids and pro-inflammatory adipokines get to metabolic tissues, including skeletal muscle and liver, and modify inflammatory responses as well as glucose and lipid metabolism, thereby contributing to metabolic syndrome. In addition, obesity induces a phenotypic switch in adipose tissue from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages. On the other hand, the adipose production of insulin-sensitizing adipokines with anti-inflammatory properties, such as adiponectin, is decreased in obese state. The red arrows indicate increased (when pointing upward) or decreased (when pointing downward) responses to obesity. ANGPTL, angiopoietin-like protein; ASP, acylation-stimulating protein; IL, interleukin; MCP-1, monocyte chemotactic protein; NAFLD, nonalcoholic fatty liver disease; PAI-1, plasminogen activator inhibitor-1; RBP4, retinol binding protein 4; SAA, serum amyloid A; SFRP5, secreted frizzled-related protein 5; TGF-β, Transforming growth factor-β; TNF-α, tumor necrosis factor-α.

Figure 3.

Schematic view of insulin signaling pathway in adipose tissue. Binding of insulin to its receptor on adipocytes triggers the phosphorylation and activation of insulin receptor substrate, which forms a docking site for phosphatidylinositol 3-kinase (PI3K) at the membrane. When docked, PI3K converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate, a second messenger that activates phosphoinositide-dependent protein kinase 1 and recruits Akt (also known as protein kinase B, PKB) to the cell membrane. Consequently, PI3K-AKT/PKB signaling pathway regulates metabolic processes. The red arrows indicate up-regulation (when pointing upward) or down-regulation (when pointing downward) in response to PI3K-AKT/PKB signaling pathway. The Ras-mitogen-activated protein kinase pathway leads to the activation of genes which are involved in cell growth, thereby promoting inflammation and atherogenesis. IRS-1, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PDK, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKB, protein kinase B.

Figure 4.

Mechanisms of dyslipidemia in obesity. An increased free fatty acids (FFA) release from adipose tissue via lipolysis can result in enhanced delivery of FFA to the liver. The enhanced FFA leads to increased triglyceride (TG) and very-low-density lipoprotein (VLDL) production in the liver as well as inhibition of lipoprotein lipase in adipose tissue and skeletal muscle, thereby promoting hypertriglyceridemia. Moreover, the increased VLDL in the liver can inhibit lipolysis of chylomicrons, which also contributes to hypertriglyceridemia. The TG in VLDL is exchanged for cholesteryl esters from low-density lipoproteins (LDL) and high-density lipoproteins (HDL) by the cholesteryl ester transport protein, producing TG-rich LDL and HDL. The TG in the LDL and HDL is then hydrolyzed by hepatic lipase, producing both small, dense LDL and HDL. The decreased HDL concentration and formation of small, dense LDL particules are linked to a higher risk of cardiovascular disease. The red arrows indicate increased (when pointing upward) or decreased (when pointing downward) responses to obesity. CE, cholesteryl esters; CETP, cholesteryl ester transport protein; FFA, free fatty acids; HDL, high-density lipoproteins; HL, hepatic lipase; LDL, low-density lipoproteins; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very-low-density lipoprotein.

Figure 5.

The Multi-hit hypothesis of NAFLD pathogenesis. The “first hit”, such as insulin resistance and lipid metabolism dysregulation, leads to the development of simple steatosis and renders hepatocytes susceptible to “multi-hit”, which include gut-derived bacterial toxins, adipocytokine imbalance, mitochondrial dysfunction, oxidative damage, dysregulated hepatocyte apoptosis, activation of pro-fibrogenic factors and pro-inflammatory mediators and hepatic stellate cell activation, ultimately leading to NASH and cirrhosis. The red arrows indicate up-regulation (when pointing upward) or down-regulation (when pointing downward) in response to insulin resistance.