HDAC1 deacetylates PGC-1α and its inhibition improves glucose homeostasis in diet-induced obese mice

Excessive hepatic glucose production (HGP) driven by increased gluconeogenesis is a hallmark of type 2 diabetes, making its inhibition a crucial strategy for reducing hyperglycemia. Central to HGP regulation is the transcriptional coactivator proliferator-activated receptor gamma coactivator 1α (PGC-1α), which promotes the expression of key gluconeogenic enzymes. The acetylation state of PGC-1α significantly influences its coactivating potential, with increased acetylation-whether induced genetically or chemically-shown to suppress its gluconeogenic activity and lower hyperglycemia. The delicate balance between specific acetyltransferases and deacetylases determines the acetylation status of PGC-1α and, consequently, its activity. Although the role of sirtuin deacetylases in PGC-1α acetylation has been extensively studied, zinc-dependent histone deacetylases (HDACs) have received less attention in this context. In this study, we demonstrate that HDAC1 strongly deacetylates PGC-1α, enhancing its ability to coactivate the transcription factor hepatic nuclear factor 4α. Furthermore, we show that depleting <i>Hdac1</i> in mouse primary hepatocytes and liver tissue reduces glucose production, consistent with decreased PGC-1α activity. Although the HDAC family has been investigated for their contributions to metabolic homeostasis, our findings reveal a specific mechanistic pathway by which HDAC1 modulates glucose homeostasis.<b>NEW & NOTEWORTHY</b> We identify HDAC1 as a regulator of PGC-1α acetylation and gluconeogenic activity in hepatocytes. Genetic depletion of HDAC1 increases PGC-1α acetylation in hepatocytes and reduces hepatic glucose production, revealing a previously unrecognized mechanism for glucose homeostasis. These findings highlight HDAC1 as a potential therapeutic target for type 2 diabetes.