We described a variety of nutritional manipulations that modulate the activities of lipogenic enzymes and flux through the pathway for fatty acid synthesis. Insulin, glucagon, T3, glucocorticoids, glucose, and fatty acids are probably the primary humoral factors involved in signaling changes in nutritional status of an intact animal to liver and adipose tissue. Allosteric and covalent modification mechanisms regulate minute-to-minute flux from glucose to long-chain fatty acids by regulating the catalytic efficiency of key enzymes, including 6-phosphofructo-1-kinase, L-pyruvate kinase, pyruvate dehydrogenase, and acetyl-CoA carboxylase. Considerable progress has been made in identifying the protein kinases and phosphatases that regulate the state of phosphorylation of these enzymes. Regulation of gene transcription and the resultant alterations in enzyme activity account for long-term adaptive control of lipogenesis. Although the molecular details are not known, the same allosteric effectors, protein kinases, and phosphatases that regulate catalytic efficiency also may regulate gene transcription by controlling the activities of specific trans-acting transcription factors. Many of the relevant transcription factors may also be involved in growth regulation. Identification and characterization of the physiologically relevant protein kinases and phosphatases will continue to be a major area of investigation vis-a-vis phosphorylation-dephosphorylation mechanisms and the short-term control of fatty acid synthesis. Characterization of the primary structure of phosphorylation sites has been a powerful tool in such investigations. Future studies will probably employ homologous recombination to introduce specific mutations into proteins of intact cells or animals. Such experiments have the potential to define not only the important modifying enzymes in a signaling pathway but also the physiological significance of the modification to regulation of flux through the fatty acid synthesis pathway. Similar approaches should be possible to define the importance of allosteric regulatory mechanisms. At the level of gene expression, we expect that identification of cis-acting DNA elements and trans-acting factors involved in the regulation of transcription of the lipogenic genes will be the predominant form of research in the near term. Trans-acting transcription factors interact with the DNA, with each other, and with the signaling pathways to bring about an integrated response to many different signals. Characterization of the functions of trans-acting factors and the mechanisms by which their activities are regulated will be an important area of future work. The long-term goal of these analyses will be to trace the intracellular signaling pathways from the nucleus to the cytoplasm and to define the sites of interaction of relevant humoral factors with the cell.
