PFKFB3/iPFK2 links nutrient metabolism and overnutrition‐associated adipocyte inflammatory response through controlling oxidative stress

Abstract

Overnutrition‐associated adipose inflammation is a common cause of many metabolic diseases such as diabetes and atherosclerosis. However, precisely how overnutrition disturbs nutrient metabolism to stimulate the adipocyte inflammatory response remains unknown. The objective of this study is to elucidate the molecular link between nutrient metabolism and the adipocyte inflammatory response. In adipocytes, PFKFB3/iPFK2 is a master regulator of nutrient metabolism. Using cultured 3T3‐L1 adipocytes, we showed that knockdown of PFKFB3/iPFK2 caused a decrease in the rate of glucose incorporation into lipid. Additionally, knockdown of PFKFB3/iPFK2 increased inflammatory signaling through JNK and NFκB p65 and enhanced the production of proinflammatory cytokines. These effects were accompanied by an increase in the production of reactive oxygen species (ROS) under both basal and palmitate‐stimulated conditions, indicating increased oxidative stress. When treated with etomoxir, an inhibitor of fatty acid oxidation, the production of ROS in PFKFB3/iPFK2‐knockdown adipocytes was lowered down to the levels comparable with those brought about by N‐acetyl‐L‐cysteine, a compound that suppresses most pathways for ROS production. Together, these data suggest that PFKFB3/iPFK2 links nutrient metabolism and overnutrition‐associated adipocyte inflammatory response by controlling oxidative stress.Grant Funding Source: none