Metabolite 2-aminoadipic acid: implications for metabolic disorders and therapeutic opportunities

Abstract

Previous evidence has indicated that the role of 2-aminoadipic acid (2-AAA), a derivative of lysine catabolism, in mediating specific detrimental effects on glial cells, notably inhibiting astrocyte activation. In addition, intrathecal administration of 2-AAA has demonstrated significant efficacy in relieving mechanical hyperalgesia. With the growing application of metabolomics in biomedical research, substantial evidence now underscores 2-AAA's pivotal role in regulating glucose and lipid metabolism. As a novel biomarker, 2-AAA is linked to increased susceptibility to diabetes and has emerged as a critical regulator of glucose homeostasis. This review explores recent advancements in understanding 2-AAA's potential therapeutic applications, particularly in the context of metabolic diseases such as diabetes, obesity, and atherosclerosis. It also addresses existing research gaps and outlines future directions for developing 2-AAA-based therapies.

Keywords: 2-aminoadipic acid; atherosclerosis; diabetes; lysine metabolism; obesity.

FIGURE 1

Metabolic pathway of lysine catabolism.

FIGURE 2

(A) 2-Aminoadipic Acid as a Marker of Cardiovascular and Metabolic Diseases.2-AAA is positively correlated with glycoxidative damage, insulin release, and body mass index (BMI), and negatively correlated with high-density lipoprotein cholesterol (HDL-C) and insulin sensitivity. (B) Potential Mechanisms of 2-AAA in Insulin Secretion and Lipolysis. This schematic illustrates the proposed pathways by which 2-AAA affects insulin secretion and lipolysis. The primary sites of 2-AAA action are pancreatic β-cells and adipocytes. In pancreatic β-cells, 2-AAA facilitates insulin secretion by regulating the transcription of crucial genes involved in insulin production (Ins1 and Ins2), glucose uptake (Glut2), glucose metabolism (Gck, Pcx), and insulin biosynthesis. Additionally, in adipocytes, 2-AAA overstimulates β3-adrenergic receptor signaling, leading to enhanced lipolysis and thermogenesis.