Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.
Nencki Institute of Experimental Biology, PAS, 02-093 Warsaw, Poland.
Genes Dev. 2020 Apr 1;34(7-8):495-510. doi: 10.1101/gad.333617.119. Epub 2020 Mar 5.
Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.
肥胖引起的糖尿病影响全球超过 4 亿人。失控的脂解（脂肪细胞中游离脂肪酸的释放）可能导致糖尿病和肥胖。为了确定针对该途径的未来治疗方法，我们进行了高通量筛选，发现细胞外调节激酶 3（ERK3）是一个命中目标。我们证明β-肾上腺素能刺激稳定 ERK3，导致与辅助因子 MAP 激酶激活的蛋白激酶 5（MK5）形成复合物，从而驱动脂解。从机制上讲，我们确定了 ERK3/MK5 途径的下游靶标，转录因子 FOXO1，它促进主要脂解酶 ATGL 的表达。最后，我们提供的证据表明，ERK3 在小鼠脂肪细胞中的靶向缺失抑制脂解，但会增加能量消耗，促进瘦体型并改善糖尿病。因此，ERK3/MK5 代表脂肪组织中以前未被识别的信号轴，是未来旨在对抗肥胖引起的糖尿病的治疗方法的一个有吸引力的目标。
