Jan-Wilhelm Kornfeld is Professor at the University of Southern Denmark (SDU). His scientific interest revolves around the question why higher organisms like humans or mice ‘invest’ a great deal of cellular to express thousands of non-protein-coding or ‘noncoding’ RNAs and if noncoding transcripts are required for energy homeostasis in health and metabolic disease. We are particularly interested and metabolic disease. In a recent study we found that a new class of noncoding RNAs termed Long Noncoding RNAs (LncRNAs) is profoundly downregulated by obesity and type 2 diabetes in livers from human patients and C57BL/6 mice. Mechanistically, we observed that in obesity, but also upon acute refeeding, a high MAFG transcription factor activity restricts LncRNA expression, whereas in fasting LncRNAs are induced. Downstream of MAFG, we studied the liver-specific LncRNA LincIRS2 and found that glycemic excursion but also the transcription of genes required for glucose homeostasis during fasting-refeeding transition are misregulated in livers of LincIRS2-null mice.
In conclusion, our work suggests that MAFG controls a key bifurcation point in cellular homeostasis, in which low nutrient states translate into low MAFG signaling activity which in turn favors energy-preserving processes like LncRNA / LincIRS2 transcription. Under calorie-rich conditions, high MAFG signaling activity is required for full activation of mTOR-4EBP1 signaling, which ultimately favors anaplerotic, but energy-demanding processes like cellular proliferation and protein synthesis.