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 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. 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.