S6K1 controls adiponectin expression by inducing a transcriptional switch: BMAL1-to-EZH2

Adiponectin (encoded by Adipoq ), a fat-derived hormone, alleviates risk factors associated with metabolic disorders. Although many transcription factors are known to control adiponectin expression, the mechanism underlying its fluctuation with regard to metabolic status remains unclear. Here, we show that ribosomal protein S6 kinase 1 (S6K1) controls adiponectin expression by inducing a transcriptional switch between two transcriptional machineries, BMAL1 and EZH2. Active S6K1 induced a suppressive histone code cascade, H2BS36p-EZH2-H3K27me3, leading to suppression of adiponectin expression. Moreover, active S6K1 phosphorylated BMAL1, an important transcription factor regulating the circadian clock system, at serine 42, which led to its dissociation from the Adipoq promoter region. This response resulted in EZH2 recruitment and subsequent H3K27me3 modification of the Adipoq promoter. Upon fasting, inactivation of S6K1 induced the opposite transcriptional switch, EZH2-to-BMAL1, promoting adiponectin expression. Consistently, S6K1-depleted mice exhibited lower H3K27me3 levels and elevated adiponectin expression. These findings identify a novel epigenetic switch system by which S6K1 controls the production of adiponectin, which displays beneficial effects on metabolism. Endocrinology: Revealing the regulation of a fat-derived hormone Insights into the regulatory machinery controlling production of the hormone adiponectin could guide development of treatments for various metabolic disorders. Fat cells secrete adiponectin in response to nutrient deprivation as well as circadian cues, and evidence suggests this hormone is protective against diabetes, obesity, and hypertension. Sang Ah Yi from Sungkyunkwan University, Suwon, South Korea and colleagues have determined that a protein called S6K1 plays a central role in governing adiponectin production. They show that S6K1 maintains the adiponectin gene in an inactive state via a two-pronged inhibitory mechanism. S6K1 interacts closely with both the cellular circadian clock and other epigenetic pathways, and is inactivated by fasting conditions, allowing adiponectin synthesis to proceed. These regulatory pathways could offer a useful target for therapeutic efforts aimed at boosting adiponectin production.