The quantum physicist Erwin Schrodinger surmised in his monograph “What is Life?” that the organized matter known as life needs to feed on “negative entropy” to avoid decay.1 He concluded that this feeding on negative entropy is achieved through metabolism, a term derived from Greek that describes an exchange of materials. Because of this centrality to life, metabolism’s core pathways—glycolysis and respiration—evolved early in Earth’s history and are highly conserved. At every stage of life, metabolism provides the needed nutrients, energy, and building blocks. Embryogenesis, for instance, requires metabolism of maternally derived nutrients to support cellular repair, growth, division, and differentiation. In particular, cell replication requires that the instructions emanating from the DNA sequence, modulated by the epigenome, couple with the import of nutrients and metabolic pathways to produce the components and energy necessary to build two copies of a cell and maintain high replication fidelity of the genome. During growth and development, and especially during adulthood, metabolism also plays the important role of providing bioenergetics for cellular and organismal homeostasis. Metabolism can also feature prominently in disease, and this chapter discusses how the metabolic pathways central to life and normal biology can be subverted in cancer to fuel abnormal growth.
Food, through metabolism, provides the nutrients necessary for homeostasis, repair, and reproduction of many organisms. To align supply and demand, mammalian metabolism is linked to sleep cycles through the central circadian clock that senses light and dark phases of the day via the eye and central nervous system. The central regulation of feeding and sleeping cycles coordinates nutrient availability from food with the circadian oscillation of metabolism of individual cells, which all have a molecular clock comprised of a network of transcription factors that regulates cell metabolism.2
Food is digested, absorbed through the gastrointestinal tract, and in part processed or stored in the liver, which is a key metabolic organ.3 Processed lipids in the form of lipoproteins are synthesized in the liver and disseminated throughout to supply the needs of various organs. Amino acids, with glutamine circulating at the highest level (0.5 mM), supply cells with building blocks for proteins. Some amino acids (nonessential) are synthesized by humans, but essential amino acids must be available from the diet. Complex carbohydrates are broken down and circulate as glucose, a vital nutrient for virtually all mammalian cells. In this regard, an endocrine system (insulin and glucagon) has evolved to control the circulating levels of this precious bioenergetic molecule. When in excess, amino acids and sugars contribute to lipogenesis, and the extra energy is stored as fat depots in adipose tissues. Excess glucose is stored as glycogen, which is deployed to release glucose in starved conditions. It is believed that, during our evolution, periods of gorging and feeding were separated by significant durations of starvation; hence, we have evolved mechanisms to survive starvation.
In contrast to the fed state, when insulin level increases in response to rising glucose to ...