Research Perspective Volume 4, Issue 2 pp 98—115

Figure 1. Brain stress and inflammation in the development of metabolic syndrome. Overnutrition in the forms of high circulating levels of glucose, free fatty acid (FFA), and amino acids (AA) is the predominant pathogenic inducer of central metabolic inflammation. Excessive nutrients transported into cells can pose severe stresses on cellular metabolic machinery, affecting organelles such as mitochondria and endoplasmic reticulum (ER) which are responsible for nutrient oxidation and protein synthesis, respectively. As a result, intracellular reactive oxygen species (ROS) increase due to heightened mitochondrial activities, leading to intracellular oxidative stress. In parallel, high levels of cellular metabolic activities demand increased protein synthesis and folding by ER, leading to ER stress. Additionally, high levels of intracellular ROS from oxidative stress can escalate ER stress. Prolonged oxidative stress and ER stress can cause intracellular accumulation of dysfunctional mitochondria, ER, and other cytosolic proteins, leading to increased autophagy stress and autophagic defect. All these intracellular stresses are activators of cellular proinflammatory kinases, among which IκB kinase (IKK) and c-Jun N-terminal kinase (JNK) have been implicated. Activation of these proinflammatory pathways leads to transcription of inflammatory response genes via nuclear transcription factors NF-κB and AP-1. ER stress can also directly induce transcription of inflammatory genes via activating transcription factor X-box binding protein-1 (XBP1). Certain extracellular nutrient species can bind to toll-like receptors to activate intracellular proinflammatory signaling. Furthermore, local or systemic inflammatory cytokines can reinforce metabolic inflammation via cytokine receptor signaling. Such collective onset of cellular inflammation impairs normal cellular functions, leading to central dysregulation of various physiological processes across energy balance, glucose tolerance, and cardiovascular homeostasis, which underlies the development of metabolic syndrome and related diseases.