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Transcription of the gene for PEPCK-C occurs in a number of mammalian tissues, with highest expression occurring in the liver, kidney cortex, and white and brown adipose tissue. Several hormones and other factors, including glucagon, epinephrine, insulin, glucocorticoids and metabolic acidosis, control this process in three responsive tissues, liver, adipose tissue, and kidney cortex. Expression of the gene in these three tissues in regulated in a different manner, responding to the specific physiological role of the tissue. The PEPCK-C gene promoter has been extensively studied and a number of regulatory regions identified that bind key transcription factors and render the gene responsive to hormonal and dietary stimuli. This review will focus on the control of transcription for the gene, with special emphasis on our current understanding of the transcription factors that are involved in the response of PEPCK-C gene in specific tissues. We have also reviewed the biological function of PEPCK-C in each of the tissues discussed in this review, in order to place the control of PEPCK-C gene transcription in the appropriate physiological context. Because of its extraordinary importance in mammalian metabolism and its broad pattern of tissue-specific expression, the PEPCK-C gene has become a model for studying the biological basis of the control of gene transcription.

Regulation of the turnover of triglycerides in adipose tissue requires the continuous provision of 3-glycerophosphate, which may be supplied by the metabolism of glucose or by glyceroneogenesis, the de novo synthesis of 3-glycerophosphate from sources other than hexoses or glycerol. The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. To accomplish this, we mutated the binding site for the peroxisome proliferator-activated receptor ␥ (PPAR␥) called the peroxisome proliferator-activated receptor element (PPARE), in the 5 flanking region of the PEPCK-C gene in the mouse by homologous recombination. The mutation abolished expression of the gene in white adipose tissue and considerably reduced its expression in brown adipose tissue, whereas the level of PEPCK-C mRNA in liver and kidney remained normal. Epididymal white adipose tissue from these mice had a reduced triglyceride deposition, with 25% of the animals displaying lipodystrophy. There was also a greatly reduced level of lipid accumulation in brown adipose tissue. A strong correlation between the hepatic content of triglycerides and the size of the epididymal fat pad in PPARE ؊/؊ mice suggests that hepatic triglyceride synthesis predominantly utilizes free fatty acids derived from the adipose tissue. Unlike other models, PPARE ؊/؊ mice with lipodystrophy did not exhibit the lipodystrophy-associated features of diabetes and displayed only moderate hyperglycemia. These studies establish the importance of the PPARE site for PEPCK-C gene expression in adipose tissue and the role of PEPCK-C in the regulation of glyceroneogenesis, a pathway critical for maintaining the deposition of triglycerides in adipose tissue.