SAPS3 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge

Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanism underneath that is not clear. Here, we demonstrate serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is an essential negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Remarkably, either whole-body or liver-specific deletion of SAPS3 protects mice against the HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a critical negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes. Overall design: To investigate the gene expression profiling exhibited in the livers of mice lacking serine/threonine protein phosphatase 6 regulatory subunit 3, SAPS3, and fed an high fat diet (HFD), we performed RNA sequencing using liver tissues that were collected from ppp6r3fl/fl (FF) mice and liver-specific SAPS3 knockout mice (LKO) following 16 weeks on HFD.