The immune response and metabolic regulation are highly integrated, and their interface maintains a homeostatic system. Their dysfunction can cause obesity and its comorbidities, including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). Endoplasmic reticulum (ER) stress is a central abnormality linking obesity, insulin resistance, and NAFLD. ER stress in response to increased hepatic lipids may decrease the ability of the liver to secrete triglyceride by limiting apolipoprotein B secretion, thereby worsening fatty liver. Overnutrition or obesity activates the innate immune system, with the subsequent recruitment of immune cells that contributes to the development of insulin resistance. A significant advance in our understanding of obesity-induced inflammation and insulin resistance has been a recognition of the critical role of adipose tissue macrophages. A role for chemokines, small proteins that direct the trafficking of immune cells to sites of inflammation, has also been demonstrated. Chemokines activate the production of inflammatory cytokines through specific chemokine receptors. This review highlights the chemokine systems linking obesity to inflammation and insulin resistance. Treatment options that target immune cells with the aim of halting the development of insulin resistance and type 2 diabetes remain limited. DPP-4 inhibitors or micronutrients may contribute to the immune regulation of glucose and lipid metabolism by regulating macrophage polarization, thereby reducing insulin resistance and preventing the progression of NAFLD. A detailed understanding of the immune regulation of glucose and lipid homeostasis can lead to the development of a novel therapy for insulin resistance, type 2 diabetes, and NAFLD.
Keywords: Chemokine; Dipeptidyl peptidase-4; Endoplasmic reticulum stress; Insulin resistance; Macrophage; Nonalcoholic fatty liver disease.