6-Phosphogluconate dehydrogenase (6PGDH) constitutes the pentose phosphate pathway and produces NADPH. 6PGDH is also considered as a lipogenic gene since NADPH is a pivotal cofactor for lipogenesis. Thus, it is important to elucidate how 6PGDH is regulated by various signals related to energy homeostasis. Here, we provide several evidences that ADD1/SREBP1c regulates the expression of mouse 6PGDH gene. DNase I footprinting assay and point mutation studies revealed that the E-box (CANNTG) motif in the promoter of mouse 6PGDH is an important cis-regulatory element for ADD1/SREBP1c. 6PGDH mRNA is highly expressed in white adipose tissue and tightly modulated by nutritional status. Furthermore, we found that ADD1/ SREBP1c mediates insulin-dependent 6PGDH expression and that P13-kinase is an important linker for its regulation. Taken together, these data suggest that ADD1/SREBP1c is a key transcription factor for 6PGDH gene expression and would coordinate glucose metabolism and lipogenesis for energy homeostasis. (c) 2005 Elsevier Inc. All rights reserved.