Methylglyoxal affect adipose tissue metabolism throughout the formation of Advance glycation end products

Diabetes-associated hyperglycemia condition is correlated with elevated systemic levels of glucose metabolites as methylglyoxal (MGO) that affect the formation of advanced glycation end products (AGEs). AGEs creation leads to protein misfolding, aggregation, and covalent crosslinking, which amplified protein stiffness.

The motivation of the study is to understand how AGEs influence adipocytes’ niche stiffness and cellular response. We studied the effects of MGO on adipose tissue in mice and in an in-vitro model. MGO was added as a supplement in nutrition for 15 weeks resulting in an increase in mice weight, blood glucose levels, and GTT peak. We observed higher RAGE levels (AGE receptor) that indicate presence of more AGEs in the tissue. The adipose ECM mass was thicker and more collagenous and was visualized by TEM. Those parameters suggest a rise in tissue stiffness and led us to examine the hippo-signaling pathway through changes in mechano-sensing protein YAP1. MGO indeed increases YAP1 protein expression and translocates YAP1 to the nucleus in adipose tissue as well as in cultured adipocytes. In culture, the MGO led to a decrease in the mRNA level of PPARγ, LPL, and C/EBPα and overall adipogenesis. This was also associated with a reduction in GLUT4 expression on the cell membrane which lowers glucose internalization.

This study demonstrates the MGO-related AGEs creation, that affects ECM stiffness with signaling and glucose metabolism alteration. These novel findings enlighten the AGEs effects on the cells’ niche that is associated with the pathophysiology of metabolic diseases.