Patients with obesity and type 2 diabetes display elevated hepatic glucose production (HGP). Purine-rich element binding protein β (Purβ) is able to bind to purine-rich single- or double-stranded DNA or RNA, where it can act as a transcription factor or a repressor of transcription or translation. Jia et al. identify Purβ as a positive regulator of HGP. Purβ, induced by fasting or glucagon, promotes HGP by increasing Adcy6 transcription. Purβ/ADCY6 may be a promising drug target for the treatment of hyperglycemia in patients with obesity.