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.

中文翻译：

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肾上腺素能诱导的 ERK3 通路驱动脂肪分解并抑制能量耗散。

肥胖引起的糖尿病影响全球超过 4 亿人。不受控制的脂肪分解（脂肪细胞释放游离脂肪酸）会导致糖尿病和肥胖。为了确定针对该途径的未来治疗途径，我们进行了高通量筛选并将细胞外调节激酶 3 (ERK3) 确定为命中。我们证明 β-肾上腺素能刺激稳定 ERK3，导致与辅因子 MAP 激酶活化蛋白激酶 5 (MK5) 形成复合物，从而驱动脂肪分解。从机制上讲，我们确定了 ERK3/MK5 通路的下游靶点，即转录因子 FOXO1，它促进主要脂解酶 ATGL 的表达。最后，我们提供的证据表明，小鼠脂肪细胞中 ERK3 的靶向缺失会抑制脂肪分解，但会提高能量耗散，促进瘦表型和改善糖尿病。因此，ERK3/MK5 代表了脂肪组织中以前未被识别的信号轴，并且是未来治疗肥胖引起的糖尿病的有吸引力的目标。