Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.

中文翻译：

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AMP 激活的蛋白激酶激活抑制原代小鼠脂肪细胞中瘦素的表达，与脂肪形成无关

脂肪生成被定义为干细胞前体发育成成熟脂肪细胞，对于脂肪组织的扩张、周转和健康至关重要。脂肪干细胞中脂肪生成潜力的丧失或脂肪生成受损现在被认为是脂肪组织功能障碍的根本原因，并且与代谢疾病相关。在这项研究中，我们试图确定 AMP 激活蛋白激酶 (AMPK) 在脂肪生成中的作用，AMPK 是一种进化上保守的能量稳态主调节因子。在脂肪形成的关键阶段用小分子 AMPK 激活剂 (BI-9774) 处理原代小鼠脂肪干细胞，以确定 AMPK 激活对脂肪细胞定向、成熟和功能的影响。为了确定 AMPK 在这些过程中抑制脂肪生成的作用，我们比较了乙酰辅酶 A 羧化酶 (ACC) 的药理抑制作用。我们发现 AMPK 激活以时间和浓度依赖性方式抑制脂肪生成。脂肪形成承诺过程中短暂的 AMPK 激活会导致脂肪形成转录因子表达的显着的、不依赖于 ACC 的抑制。此外，我们还发现，无论脂肪生成如何，瘦素基因表达都会对短期和长期 AMPK 激活产生显着的、以前未曾探索过的抑制作用。这些发现表明，除了对脂肪生成的影响之外，AMPK 激活还可以独立于脂肪生成而关闭原代小鼠脂肪细胞中的瘦素基因表达。我们的结果通过尚未确定的机制将瘦素表达确定为 AMPK 的新靶标。