The control of blood glucose levels in vertebrates is a fundamental problem that has long intrigued both clinical and basic researchers. Much is known of the circulating hormones (eg, insulin, glucagon, and glucocorticoid) that regulate the metabolism of carbohydrate and fat. The structures of these hormones have been determined, their receptors identified, and in general terms, their modes of action are understood. Likewise, considerable information has accumulated concerning the hormone-regulated enzymes involved in the control of gluconeogenesis and the synthesis and mobilization of glycogen and triglycerides. The amino acid sequences of many of these enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), tyrosine aminotransferase (TAT), hormone-sensitive lipase (HSL), and glycerol-3-phosphate dehydrogenase (GPDH) are known, and their encoding genes have been cloned. One issue central to the problem of energy homeostasis concerns the differentiation of liver and adipose tissues, respectively, as the principal sites of carbohydrate and fat metabolism. How does the liver become specified as the organ primarily responsible for gluconeogenesis and the storage and mobilization of glycogen? How does adipose tissue become the storage depot of triglycerides? Both tissues provide the major circulating physiological fuels (glucose, free fatty acids, and ketones). What mechanisms facilitate the elevated levels of expression of gluconeogenic and lipogenic enzymes in these respective tissues? How do these enzymatic activities become subject to regulation by the hormones that control blood sugar levels?

The answers to some of these questions are beginning to emerge. For example, the abundance of PEPCK, GK, and TAT enzymatic activities in liver is correlated with relative increases in their mRNA levels. Likewise, GPDH and HSL transcripts accumulate selectively in differentiated adipocytes. What causes the genes encoding these mRNAs to be expressed at elevated levels in the appropriate cell types? Moreover, what distinguishes the PEPCK, GK, TAT, and glucose-6-phosphatase (G-6-P) genes, whose expression in liver cells is regulated hormonally, from other genes expressed in hepatocytes that are not responsive to regulation by the circulating factors that modulate energy homeostasis? In this communication we speculate that regulation of energy balance may be channeled, at least in part, through a recently discovered gene regulatory protein, termed CCAAT/enhancer-binding protein (C/EBP). The