De-Meaning of Metabolism

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Science  29 Jun 2012:
Vol. 336, Issue 6089, pp. 1651-1652
DOI: 10.1126/science.1221834

Metabolism is a hot topic in science, from the epidemic of “metabolic diseases” such as obesity and diabetes to the rediscovery of altered “cancer metabolism” as a defining characteristic of malignant cells. As is often the case, once a topic has become in vogue, its name ceases to have meaning as researchers try to identify their work as relevant to the latest fashion. Thus, it is opportune to reconsider not only the meaning of “metabolism” but also whether the rebirth of metabolic research is incorporating many of the lessons learned through years of study in the last century.

Metabolism can be defined as “the chemical processes that occur within a living organism in order to maintain life” (1). This definition makes metabolism the primary subject of biochemistry, which is “the branch of science concerned with the chemical and physico-chemical processes and substances which occur within living organisms” (2). Thus, the definitions of biochemistry and metabolism clearly overlap. One conceptual distinction is that biochemistry is the study of the metabolites themselves, while metabolism refers to the conversion of nutrients to metabolites as well as the interconversion of metabolites within the body. In that context, biochemistry is more centered on steady-state amounts, whereas metabolism is more focused on flux, although flux is determined in part by mass action. The physiological implication is that metabolism is essentially the science of molecular transformation, which incorporates biological chemistry and energetics into a context necessarily constrained by physiology. By definition, metabolism is a process largely concerned with the generation of energy by catabolism and the anabolic manufacture of cellular and extracellular constituents. Metabolism represents the essence of how organisms interact with their environment and, in doing so, overcome the thermodynamic mandate to “feed upon negative entropy” (3).

The field of signal transduction emerged from the desire to understand the effects of hormones on metabolism (4). Ironically, though modern signal transduction research is built upon principles developed through years of metabolism research, we are in danger of ignoring these lessons in the rebirth of metabolic research in the 21st century. In part, this is likely due to recent dominance of cancer metabolism, which represents a specialized situation in terms of its consideration of the tumor as an isolated entity, the cancer's intrinsic pathological state, and the unique influence on metabolism of somatic mutation followed by selection for autonomous growth and survival (5).

It follows that the most important distinction between how the term “metabolism” relates to cancer versus normal physiology and other pathological processes such as obesity and diabetes has to do with the dialogue between the single cell and the rest of the organism. A fundamental concept in molecular oncogenesis is that mutation of genes encoding intermediates in signaling pathways renders the cancer cell independent of, and unresponsive to, the normal control exerted by growth and survival factors (6). Uncontrolled growth requires fuel in the form of metabolites for which the cancer cell competes with normal cells; a cancer cell often requires more energy than the maintenance of normal cells, and the cancer cell is not programmed to adjust its fuel utilization based on the needs of the rest of the body.

Historically, a key aspect of “metabolism” is its link to “metabolic rate,” which is the amount of energy used by an organism at rest (7). The metabolic rate concept was initially related to whole-body metabolism, and particularly the consumption of oxygen in the burning of biochemical fuels to create energy. Although basal metabolic rate reflects the sum of biological processes in single cells, the interaction between cells is essential to its regulation. Though host conditions such as hypoxia and blood supply might limit the metabolic capacity of the tumor cell, there is little exchange of information between the cancer and its host organism and the tumor rarely acts as a supplier of energetically useful metabolites. In fact, the opposite is more likely, as cancer cells may deplete their host of nutrients by their own rapid fuel consumption and stimulation of a cachectic response. On the other hand, caloric restriction of the host may reduce the growth of cancer by limiting nutrient availability as well as by reducing endocrine growth factors such as insulin.


It is important to clarify the definition of metabolism as it becomes increasingly recognized as an underlying mechanism in a range of diseases.


By contrast, metabolic control in professional metabolic cells such as fat cells (adipocytes), liver cells (hepatocytes), and muscle cells (myocytes) is unlike that in tumor cells, as the biological functions of these cells involve the coordinated partitioning of nutrients throughout the body. Indeed, obesity can be thought of as a pathological increase in the storage of lipid in adipocytes, and the elevated blood glucose concentrations that define diabetes result from inadequate partitioning of glucose between tissues and the blood compartment of the body. Hormone-producing endocrine cells and their metabolic tissue targets provide homeostatic control of energy metabolism at an organismal level, whereas the growth of cancer is dependent upon the cell-autonomous acquisition of fuel that is, in general, insensitive to hormonal signals that evolved to regulate metabolism in a more balanced manner. A major discovery of recent metabolic research has been that endocrine glands are not the only organs sending out directives to classic metabolic tissues, but in fact muscle, adipose tissue and liver are engaged in constant, active conversations with each other. Nonetheless, whether the relationship between a cell and the organism in which it resides is strictly parasitic as in cancer, mutually beneficial as in the classical insulin target tissues mentioned above, or maladaptive as in obesity and diabetes, metabolism of the cell is dependent upon its environment.

Increasingly, it is becoming clear that the exquisite specificity and fine-tuning of signal transduction cannot be explained by viewing the process as composed of linear pathways of varying strength operating in parallel (8). In retrospect, this should have been abundantly clear from the lessons of intermediary metabolism—that a multitude of pathways are inextricably interconnected, and the importance of any one depends on the conditions of the moment (9). Yet there is a real danger that the renaissance of metabolism will revert to archaic generalizations about “rate-limiting steps,” often based on no more evidence than flux measurements under a single condition or, worse, quantitation of mRNA or protein concentrations of individual enzymes.

Thus, despite increased interest in metabolism, it is critical to recognize that although the cancer cell and normal cells use the same metabolic pathways, their metabolite selection and utilization rate are highly contextual. Regulating the response to available nutrients is largely cell-autonomous for the cancer cell, and adaptations frequently require a time scale dictated by somatic mutation and selection. By contrast, cells involved in classical metabolic homeostasis are highly responsive to nutritional, neural, and hormonal cues and are constantly engaged in a two-way dialogue with the organs producing such signals. Moreover, metabolism can refer to the entire sum of biological processes essential to life of a cell or organism, or to the synthesis, degradation, or redistribution of organic compounds as well as minerals that are important for life. As the scientific community continues to probe the role of metabolism in disease, it is essential that we remember which definition is most appropriate to the question at hand.

References and Notes

  1. Acknowledgments: Supported by P01 DK49210; We thank Arthur Rubenstein for helpful discussions.


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