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Postindustrial Metabolism: Fat Knowledge

Hannah Landecker

Metabolism is a term and concept established in the nineteenth century with the coming together of chemistry and animal physiol-ogy (Kamminga 1995; Bing 1971). It was, suitably enough, a metabolism for an industrial era, focused on the conversion of matter from the raw materials of nature to the products of man. Metabolism was understood as a factory, as the activity of “thousands of minute workshops,” or “a singular inward laboratory” filled with reaction- facilitating chemistry apparatus (Voit quoted in Nichols and Reeds 1991: 1889; Huxley 1869: 137). The sciences of the interconversions of matter — Stoffwechsel — were supplemented slightly later with detailed studies of bodily conversions of food to energy — Kraftwechsel — and the resulting image of “the human motor” has been well described (Rabinbach 1992). Max Rubner, a German physiologist in whose efforts lie the origins of our contemporary log-ics of the calorie — he was the first to make tables of the energy contents of foods with the direct intent of rationalizing nutrition — was deeply concerned with food as the source of bodily work (Gratzer 2005). Wilbur Olin Atwater, an American scientist trained in Germany, brought home both the techniques and the politics of Rubner’s Arbeitsphysiologie (physiology of work). Funded by industrialists inter-ested in quelling labor unrest, nutrition science and the politics of the living wage in early twentieth- century America were deeply linked in Atwater’s own tables of how much energy could be purchased for the same money in wheat versus cab-bage (Aronson 1982; Mudry 2009).

Public Culture 25:3 doi 10.1215/08992363-2144625 Copyright 2013 by Duke University Press

This material is based upon work supported by the American Council of Learned Societies and the National Science Foundation under Grant No. 1151525. Any opinions, findings, and conclusions or recommendations herein are those of the author and do not necessarily reflect the views of the National Science Foundation.

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The disorders of such industrial bodies were coined “inborn errors of metabo-lism” in 1909 and seen as one broken part in the productive machinery, such that substrate buildup could not be converted to the next step on the line (Garrod 1909).Variations on the theme included theories of metabolic sex differentiation, with males being more catabolic (breaking down the body and thus releasing energy) and females more anabolic (building up the body and storing energy), but even with such variations, every body was seen to contain the same basic metabolic apparatus (Ha 2011). Different metabolisms might run slower or faster, or they might be balanced differently, but having a metabolism was a universal — it was a defining characteristic of all life, that which allowed organisms to live as free and autonomous beings in an ever- changing environment.

Elaborating the workings of intermediary metabolism — the exact determina-tion of which enzymes and which vitamin cofactors were necessary to catalyze what reactions within the framework of the cell — contributed a great deal of detail to this image of the factory (Holmes 1992; Kohler 1977; Reynolds 2007). Small quantities of essential nutrients were thus added to the basic equation of calories in and calories out (Smith 2009). Throughout, however, the logic of catalyzed interconversion proved remarkably powerful for the twentieth cen-tury. The enduring hold of nineteenth- century metabolism on twentieth- century thought can be seen in medical and scientific settings, but also quite markedly in political theory, philosophy, and anthropology, from the legacies of Karl Marx’s theory of labor as the metabolism between man and nature, to Hans Jonas’s use of metabolism as the foundation of freedom, to Roy A. Rappaport’s notion of pig husbandry as a cultural management of a society’s energy needs (Arendt 1971; Jonas 2001 [1966]; Rappaport 1984). As such, metabolism has been — and remains — an important resource for theories of society and social functioning. In biology, metabolism was central to the practical and physical understanding of the maintenance of the individual body of the eating organism even in the face of the necessity of constantly ingesting the outside world — eating others. In phi-losophy, metabolism came to occupy a role as part of the defining line between the living and the not living; to metabolize was to live (Jonas 2001 [1966]; Dupré and O’Malley 2009).

A culturally and historically distinctive form of reasoning about how food and the body interact in and through metabolism is emerging today. Both a conceptual domain and a set of experimental practices, this new metabolism is a regulatory zone, not a factory system; it is understood to be constituted by a dynamic web of cellular signals, built by and responding to environmental information — food molecules or food’s pollutants. Its disorders are regulatory crises. It has a distinc-

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tive mode — that of the signal rather than the chemical reaction — and it has a dis-tinctive temporality. Experimental evidence and explanatory models in many dis-tinct subfields of the life sciences are harnessing metabolic regulation to the nested times of cell cycle, circadian rhythm, life cycle, and longevity in novel ways. The survival of “today’s complex organisms” is said to depend on “the robustness and functionality of the metabolic framework,” a framework that looks and sounds like the flexible networks of information engineering: “The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions” (Grüning, Lehrach, and Ralser 2010: 220).

Knowledge of metabolism in the industrial period was framed by manufactur-ing and energy; knowledge of metabolism in the postindustrial period is suffused with environmental risk, regulation, and information. A shift from the language and temporality of energetics to that of information and from a concern with manufacturing to the regulation of manufacturing might seem unsurprising, con-sidering the world. If we live in an information age, why wouldn’t our biologies? As Dimitris Papadopoulos has put it, “Every epoch has its brain” (2011: 432); in the wake of increasing intercalation of brain and gut in scientific thought, includ-ing the recasting of Alzheimer’s as “type 3 diabetes,” it follows that there will be a distinctive metabolism for this epoch (Wilson 2004; Steen et al. 2005). Thus a postindustrial metabolism might be seen as another example of the dominance of frames — we see metabolism in terms of information engineering and communica-tion networks because information has suffused biology for decades in a variety of forms from cybernetics to bio informatics and is a ubiquitous and usefully impre-cise means in both science and culture for explaining how things work. Or it could be seen as the work of metaphor, allowing the term regulation (or regulatory cri-sis) to be a conduit between economic and biological domains — or, more broadly, the manifestly historically specific nature of scientific endeavor in its porosity to cultural context. Of course; knowledge is a product of its times.

However, times are also a product of knowledge. There is no inevitability to the specific forms that metabolic science is taking today or to the way metabolism’s materialisms themselves drive configurations of what is meant or done with the term information. Metabolism is not a concept floating above time, influenced by metaphor, and imprinted by context. More than a shift from one theory to another that could be described as a history of metabolism, metabolism is in history: the material of the bodies fed by an industrialized agriculture and food-processing system built with knowledge of (industrial) metabolism subtends these conceptual shifts (Guthman 2011; Wells 2012). Postindustrial metabolism both comes after and is itself produced by industrial metabolism.

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The aim of the present analysis is a characterization of this postindustrial metabolism, as it is emerging in the biomedical sciences now.1 Such an analy-sis is relevant not just to the study of metabolism but to the emphasis today on “translational” research, particularly in American biomedicine: research that moves quickly from the realm of the laboratory to that of industry, from idea to therapy. The funding mechanisms and publishing outlets for translational research deliberately fuse ends to means, making the end goal of the research directly and explicitly shape its character from the get- go. This is not just a question of getting pure research to become applied to human life more quickly; rather, it involves reshaping the very way research is done. An accelerated time from knowledge to application or value comes about (in principle) because knowledge is always already generated to be pipeline amenable.

One pervasive end found in this landscape is treatment for obesity, diabetes, and metabolic syndrome (O’Malley and Stotz 2011). Whatever one thinks of the obesity “crisis,” the performance of causal theories of obesity is generating a great deal of research framed to be applicable to metabolic crisis management or prevention (MacKenzie 2006). While many ask the question of what causes metabolic disorder, in light of translational logic, we should reverse the formula-tion and ask instead what metabolic disorder is causing; specifically, what are its knowledge effects? Might we speak of a fat knowledge arising in the space of this particular translational economy?

In metabolism we see the perhaps unpredictable effects of the so- called diabe-sity problem (diabetes + obesity) exactly because it reaches into one of the realms of life’s basics; metabolism has been looked to by scientists, philosophers, and social scientists as a defining characteristic, a universal, a theoretical resource, a way of understanding life and the world (Landecker 2013). In looking at the specifics of this new metabolism we may understand some of the impact that the concerted practical effort to comprehend and treat metabolic disorders is hav-ing on knowledge of life. At the same time, we may also gain some insight into how the material basis of experiment and clinical practice — the metabolisms of the biomatter in the cages, dishes, and clinics of metabolic biomedical science—shape the knowledge made with them.

1. The discussion in this article is limited to the United States only because that is where my interlocutors and observations have all been located. It is open to debate whether these phenomena may be fairly characterized as an “American metabolism” even when found elsewhere, manifesting locally in different ways. Certainly, in countries like France and China, metabolic syndrome is seen as the direct result of Americanization of food and culture. See, e.g., Gilman 2008; Saguy, Gruys, and Gong 2010.

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The focus here is the relationship between food, time, and biology with the shift from metabolism as factory to metabolism as iteratively generated interface, which is also a shift from the time of energetics to the time of information. Four examples are given below, each chosen from a different temporal and spatial scale of metabolic investigation, from the momentary cellular to the intergenerational organismal. These examples are chosen out of a landscape of such work because their experimental and explanatory logics are particularly illuminating of a more general shift, summed up in Table 1, from an industrial to a postindustrial metabo-lism. The table format has both the benefit of laying out a schema to think about and the danger of proposing too stark a distinction; the entries in its columns contrast the different centers of concern found in the logic of food as fuel versus that of food as signal.

Table 1 A table of concerns

Industrial Metabolism Postindustrial Metabolism

Energy (calorie) InformationManufacturing RegulationSubstrate SignalWaste accumulation Functional asynchronyLabor and fatigue Sleeping and aging

The argument here is not that one domain of concerns is eclipsing the other entirely or that these logics are necessarily found in this configuration outside the scientific literature. Excess calorie intake without corresponding energy expenditure, for example, remains a standard explanation for obesity (Nestle and Nesheim 2011). Nonetheless, it is well worth identifying what is happening to metabolism today in research settings, exactly because the alimentary and the therapeutic are being pressed into new relations of meaning and value in ways that reconfigure both food and medicine. The four examples detailed here give a window onto this process of reevaluating food’s value as reaching far beyond that of fuel or raw material, in investigations of the molecular elements of foods or the timing of intake for their regulatory properties, rather than their caloric or nutritional value.

Marx found in the nineteenth- century science of metabolism a fecund source of inspiration for the understanding of exchange (Schmidt 1971). Things have changed, of course, in the relation of Man to Nature. Now that the task increasingly facing biomedicine is not to treat the “natural” body and its inborn errors or invading infections but to treat the bodies of humans conditioned by a world of

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their own making, suffering the predispositions and diseases of industrialized abundance, metabolism may once again be a useful resource for theorizing value (Arendt 1958).

Scale 1: Glucose to Gene

In 2009 a group of researchers at the University of Pennsylvania published an article in Science titled “ATP – Citrate Lyase Links Cellular Metabolism to His-tone Acetylation” (Wellen et al. 2009). Working with cultured cells, the find-ings were about what happens when you give cells glucose, which is the pri-mary source of energy for mammalian cells. Cells break down glucose through a process called glycolysis — the steps of the various reactions involved and the enzymes catalyzing them have been well described since the 1930s. Glycolysis is, as one commentator on the article observed, “a subject for textbooks” (Ladur-ner 2009: 18). In this textbook view, enzymes in the cellular cytosol convert the by- products of energy generation in the mitochondria into building blocks for lipids.

What these investigators showed was that some of these enzymes — they focused on one in particular called ATP – citrate lyase, or ACL — can be found in the cell’s nucleus. ACL converts one molecule to another, citrate to acetyl – Coenzyme A (acetyl- CoA). Acetyl- CoA happens to be an essential cofactor in the modifica-tion of histone proteins; its acetyl group (COCH3) is transferred to the histone in a process called acetylation. Adding these kinds of chemical groups to a protein changes its shape and its function. And histone proteins happen to be essential to the determination of the configuration of chromatin, the name given to the com-plex of DNA and proteins that compacts the very long strand of genetic material into the tiny space of the nucleus. Chromatin can loosen up or become more com-pact, affecting the availability of DNA for transcription and therefore translation (the other translation) into proteins such as metabolic enzymes.

The basic message is that a molecule assumed to be in the body of the cell busy converting one substance to another in order to store the energy taken in as food in transubstantiated form — glucose to lipids, for example — has now also been found in the nucleus, participating in gene regulation. The substrate of the metabolic process — in this case acetyl- CoA — becomes both substrate and signal: “In short, acetyl- CoA not only fulfills its primary roles as an energy currency and as a building block for lipids during cellular growth, but it also has simultaneous regulatory — one might even say signaling — functions in cellular homeostasis by determining the levels of histone acetylation. In turn, histone acetylation acts as a

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rheostat over chromatin structure and contributes to the transcriptional activation of a glycolytic metabolic program” (Ladurner 2009: 19).

To translate even further: the workaday enzymes and intermediate conversion products of metabolic cycles long ago relegated to the textbook here reemerge at the frontiers of research as complex epigenetic, post- translational actors regulating and coordinating workaday functions. “Chromatin places metabolism center stage” (ibid.). These results illuminate a “glucose- to- gene” link, wherein glucose metab-olism becomes also chromatin modification regulating glucose metabolism — sugar is linked directly to gene regulation (Rathmell and Newgard 2009). This connection to gene regulation is in turn a direct articulation with social regulation, as the specificity of different kinds of sugars (glucose, fructose, etc.) begins to matter, biologically. If sugar is as much signal as it is fuel, then both amount and kind matter, leading to calls for regulation and taxation of sugar generally or soda specifically (Lustig, Schmidt, and Brindis 2012).

Some of the difficulty of grasping the social significance of this biochemically arcane object lies not in the technical nature of the material and the acronyms but in understanding the surprise this finding has generated or the timbre of the way it is being mobilized — with a note of triumph — as a “missing link” piece of evidence between the macroenvironmental and physiological scale of diet and eating and the molecular biochemical, DNA – near scale of gene regulation (Hoch-berg et al. 2011). To the outside observer it might not seem so surprising that a substance should participate in the regulation of its own utilization; that seems a basic principle of feedback, a concept which the life sciences have had full access to and made extensive use of for decades. Or it might seem rather obvious that the external world, the environment, should impinge on gene regulation in a rather direct fashion. However, as one researcher put it, “one field etiolated by the cloud of molecular biology has been metabolism” (McKnight 2010: 1338). I would add that the (extremely gendered) separation of the “housekeeping” from the “execu-tive” functions of the cell at the origin point of notions of genetic regulation in the middle of the twentieth century probably has something to do with the difficulty of seeing metabolic activities as complex gene regulatory activities, since meta-bolic functions have historically been classed under “housekeeping” — essential but boring.

The larger frame around the particular molecules described above — ACL and acetyl- CoA — is the clinical question of how fatness in people is linked to cancer. The context of cancer metabolism research is important; it illustrates how the turn to metabolic elements as regulators (or elements of dysregulation) is rooted in a very material change to the bodies, tissues, and cells in clinics and biomedi-

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cal laboratories. These clinical manifestations, according to researchers actively pursuing what they call a “metabolic centric way of thinking about the pathogen-esis of cancer,” are changes to cells that are seen only in the bodies of overweight subjects: “When people get fat we end up with this interesting induction of our hormonal system that we are just learning about through the world- wide obesity epidemic” (Vincent, Dass, and Thompson 2012: 486).

Why are researchers culturing cells in a nutrient medium of excess glucose? Because they believe it to be an experimental image of humans in the contempo-rary world: “We never saw the obesity associated component of carcinogenesis until people started getting refrigerators and as they became popular we started to overeat and each generation for three generations got bigger” (ibid.). Glucose has gotten to the gene — not that it wasn’t always there, but the recognition of this relationship in scientific and molecular terms has to do with its manifesta-tions clinically, culturally, politically, and scientifically. The world, including its refrigerators, has gotten to the gene via the bodies to which contemporary Western medicine is ministering: treatments for illnesses of fat are the ends of translational research, and cells cultured in excess glucose are the means fashioned to under-stand these illnesses.

A self- sufficient genome with its own executives hardly takes account of the world and certainly leaves little room for consideration of either refrigerators or other aspects of the human industrialized environment in discussions of gene expression or for the post- translational interactions of proteins with one another in acts of phosphorylation, acetylation, and so on. It was a hierarchy that saw regulatory genes and their proteins running metabolism; now one sees a con-trasting insistence that metabolic elements themselves can regulate the regulators. And metabolic elements, in turn, carry the world into the body, because they are formed through what a body ingests. For example, discussions of the “acetylome” foreground protein modifications mediated by enzymes whose actions are deter-mined by energy balance in cells that is in turn determined by food intake and, as elaborated below, by the timing of food intake (Norris, Lee, and Yao 2009). In the details of the “glucose- to- gene” link we see the generation of a certain kind of object — the substrate that is also a signal.

Scale 2: Sirtuins

The substrate-to-signal transition is also visible in a second example, the acti-vation of animal sirtuin proteins by biochemical substances found in plants. Instead of food providing nutrients and building blocks, plant matter provides

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an informational signal to the animal body and affects cell fate decisions and gene expression. The logic of this section involves three central terms: calorie restriction, sirtuin proteins, and plant secondary metabolites. Calorie restric-tion in experimental organisms from yeast to mice seems to protect against dis-orders that accompany aging and, controversially, extends life span. These posi-tive effects are mediated by sirtuin proteins (Houtkooper, Prinen, and Auwerx 2012). The amount and activity of sirtuins, which seem to kick into action under conditions of reduced nutrition, can be increased by ingestion of certain second-ary metabolites of plants. These are substances plants produce under conditions of environmental stress, for example drought or infection. Sirtuin- activating, calorie- restriction mimicking substances such as resveratrol (a molecule found in the skins of red grapes, as well as in peanuts and berries) have been the object of much academic and pharmaceutical interest: the hope is to put calorie restriction in a pill, to mimic the positive health effects of limiting the diet by up- regulating sirtuin action, without actually dieting. In other words, signaling food shortage in a time of food abundance, deep in the cell.

The sirtuin “family” is a group of proteins that share similar structures widely conserved across species. Humans have at least seven kinds of sirtuins; their dysregulation has been implicated clinically in everything from stress response to Alzheimer’s disease to cancer (Sebastian et al. 2012). At a molecular level, sirtuins catalyze a reaction that takes acetyl groups off of other proteins — they are known as deacetylases. As indicated above, acetylation and deacetylation are important to the regulation of gene expression. Sirtuin activity depends on a metabolic cofactor, nicotinamide adenine dinucleotide (NAD+), which donates or accepts electrons in chemical reactions. NAD+ is itself a product of other meta-bolic pathways, and the amount of it in a cell fluctuates according to the nutritional state of the organism. Sirtuins are seen as “sensors of a cell’s metabolic state” because their action is so closely tied to NAD+ availability (Vaquero 2009: 304).

Sirtuins are sensors that regulate. They participate in determining whether a cell goes through cell division or into programmed cell death, particularly under conditions of reduced nutrition — they are part of the “metabolic steering of cell proliferation and death” (Buchakjian and Kornbluth 2010: 715). They operate at the scale of the cell and the time of the cell cycle. The time of the cell cycle, in turn, is linked to nature and length of the life span in studies of sirtuins. Where glucose metabolism provided the surprise that metabolic intermediaries have a direct role in regulation of the genes involved in metabolism, the example of sirtu-ins extends the regulatory role of metabolites to processes farther afield: cell cycle

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regulation, cell division, cell death, oxidative stress response, immunity, aging, and longevity. They stand as a hinge point between internal regulation of diverse cellular processes and external sensing via “reading” the cell’s nutritional state (Howitz et al. 2003). In other words, metabolites do not loop back just to regulate metabolism itself but act as signals that ramify through many other regulatory processes. The exact biology of sirtuins is contested; recently there has been some retreat from claims about sirtuins and longevity to the safer territory of increas-ing the health span of a life. I have no wish to weigh in on the correctness of this or that point. What is more important is the very existence of a conceptual and practical articulation point of plant metabolism, animal metabolism, cell cycle, and life span.

The first sirtuin was characterized as a modulator of life span in yeast cells. Yeast life span can be extended by calorie restriction — but not if the function of one key sirtuin gene is knocked out (Lin, Defossez, and Guarente 2000); in other words, the sirtuin molecule somehow mediates the effect of reduced food. Since sirtuins are necessary to the claimed positive effects of calorie restriction, they appear to be a point of leverage between diet and longevity. In mammals, sir-tuin function is dampened by high food availability resulting in “excess glucose” for body cells, and conversely sirtuin activity is increased under conditions of dietary restriction (Guarente 2011: 151). The function of a gene is often investi-gated by a “knock- out” experiment; organisms such as yeast or mice that have had one or other of their sirtuins deleted by genetic engineering suffer from genome instability, high sensitivity to ionizing radiation, and early aging — including dis-orders associated with aging such as hearing loss (Someya et al. 2010). This has cemented the notion that sirtuins’ manifold effects are protective against aging.

Calorie restriction does not come easily to humans, and this is where the search for plant- derived substances that activate sirtuin proteins — and the production of synthetic activators as well — comes in. And the logic of the sirtuin activator is that of a metabolite that functions as a signal at one time that ramifies from cel-lular life cycles to organismal life spans. The theoretical framework that has been proposed for the ability of plant substances to modulate animal sirtuin activities is the theory of xenohormesis — the idea that secondary metabolites produced by plants only under environmentally stressful conditions, such as resveratrol, the polyphenols found in green tea, and circumin, are meaningful in the bodies of ani-mals in part because “an animal or fungal species uses chemical cues from other species about the status of its environment or food supply to mount a preemptive defense response that increases its chance of survival” (Howitz and Sinclair 2008: 387). In other words, plants “warn” animals about nascent stressful environmen-

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tal conditions. This is why, it is proposed, plant “signaling molecules interact directly with animal enzymes and promote health despite having no apparent homolog or chemical relative in animals” (Howitz and Sinclair 2008: 388). In other words, animals and fungi have evolved to take advantage of food as a form of environmental information, thus providing a target for anti- aging medicine for the populace that suffers an ad libitum food environment. It is as though we are seeking to extract and concentrate the effects of evolution in order to counter the ills of industrialization, quite literally, thinking about these objects as therapy for a populace maladapted to its modern environment.

Scale 3: The Food- Entrainable Oscillator

Scale 1 and scale 2 involve the invocation of food as signal, in particular glucose. Both might be characterized as biologies of the disorders of excess glucose. In this third example, when matters more than how much. That the timing of food intake, or even its rhythmicity, should matter as much as (or more than) its sub-stantive content or its quantity is emerging in studies of the eating organism in the circadian rhythms of day and night. At this intersection of the space of the organ-ism and the time of eating, we find an odd object called the “food- entrainable oscillator” (FEO), an as- of- yet unidentified physical location in the body where the rhythmic, periodic intake of food tunes a kind of molecular clock that in turn runs gene expression in distinct cycles. This molecular clock is theorized as an innate biological timekeeper that is nonetheless set by external cues—in this particular case, by eating. The FEO represents the emergence of the idea that the periodicity and frequency of eating, not just the quantity or the content of the diet, is of central importance to the body.

One reason that the connections between sirtuin biology, calorie restriction, and longevity discussed above are controversial is the observation that almost all laboratory rodents in the United States are “metabolically morbid” (Martin et al. 2010). They eat ad libitum, are not given exercise wheels or much space, and in general live the nutrient- dense, plastic- suffused lives of their human keepers. It has not seemed necessary to pay attention to housing conditions under the regime of the gene and the internal determination of biology, in which breeding mattered but not so much feeding (Davies 2011). Just going to a regime of periodic feeding rather than ad libitum cage supply extends the life span of the control rodent con-siderably; add an exercise wheel and the effect is greatly magnified, as most mice given a wheel will run a half to two and a half miles a night. What exactly is being restricted and extended in calorie- restriction experiments, then, is debatable.

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When experimental mice or rats are given food for only a limited period at the same time once a day for many days in a row, they begin to show a pattern of behavioral change shortly before that time, such as changes in body tempera-ture, a marked increase in activity, and increased frequency of approaches to the place where food is put in the cage. These changes in behavior appear before the food does, without any external indicators to clue the rodents in to the imminent meal. In the absence of any other environmental cues — no changes in light, no smells — this pattern of anticipatory rhythmic change in activity persists even if the food is stopped. The periodicity can be instilled with food, to a limit — food cycles between twenty- two and thirty- one hours can “entrain” anticipatory behav-ior, but not below or above those limits. Thus the idea of an oscillator: something that oscillates such that periodic gene expression produces physiological effects that in turn produce behavior change at particular times (Mendoza et al. 2010). Given the lack of other cues of any kind, it is assumed that a “body clock” entrain-able by food is driving the behavior, and this has been entified as “the food- entrainable oscillator,” even though, to date, nobody can find “it”: “Understand-ing the effects of food on the circadian system is complicated by the presence of another somewhat mysterious oscillator, the food- entrainable oscillator (FEO). . . . The anatomical location of the FEO is still not clear. Multiple lesion studies (ablation of the adrenals, hypothalamic structures, hippocampus, amygdala, and nucleus accumbens, among others) have failed to abolish this activity” (Green, Takahashi, and Bass 2008: 733).

Circadian biology has gone through something of a renaissance with the molecularization of the physiology of sleeping and waking (Wolf- Meyer 2012; Cambrosio and Keating 1983). The image it has generated is of a body filled with molecular clocks. We do not generally think about what our genes are doing while we’re sleeping, but it is estimated that 10 – 20 percent of genes in human tissues show a circadian rhythm of expression — active only at certain times of the day/night cycle. In this field, the image of a “network of clock genes” is dominant; it is a network synchronized by the rising and setting of the sun and other environ-mental stimuli including eating. Clock genes are sensitive to these environmental signals and relay them on, switching on or off other genes under their regula-tory control. A 2007 review called “Lifelong Circadian and Epigenetic Drifts in Metabolic Syndrome” illustrates how metabolic syndrome is increasingly being framed as an unlocking of the tight links between the various molecular clocks in the body, due to the unnatural timing cues that come from living in contemporary society:

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Links have been found between circadian rhythms and major components of energy homeostasis, thermogenesis and hunger- satiety, rest- activity rhythms and the sleep- wake cycles. Thus poorly adapted behavior and desynchronized cues may disturb the modulation of gene expression. This functional asynchrony may ultimately lead to persistence of aberrant and unphased “locking” or “leakage” of gene expression and inadapted responses in the body as a whole. . . . The present epidemic may be attributed to recent, complex lifestyle changes, including overnutrition and sedentarity, and to a host of changes of unknown impact. These include changes in the amount, type and rhythm of activity and rest, with an increasing prevalence of knowledge- based work and shift work, leisure activities with more time spent in front of a screen as opposed to read-ing, with napping often restricted by social constraints and decreases in the dynamic range and variation of environmental cues (zeitgebers). The timing of sleep has changed with industrialization and most people suffer sleep deprivation during the working week. (Gallou- Kabani, Vigé, and Junien 2007: 137)

At this intersection of circadian biology and metabolic studies, a junction that has been called “the meter of metabolism” ties the timing of appetite and eating to the time of sleeping and waking (Green, Takahashi, and Bass 2008). It is not a hierarchical image, that eating dictates sleep- wake cycles, or the reverse, but an interlocking relation that is itself in dynamic interaction with the environment. Again, we see this shift in ontological and theoretical approaches to understanding life — sleep and metabolism exist in a regulatory relation to each other — emerging out of practical experiments in which organisms or cells are fed an image of the contemporary human diet. For example, male mice fed a high- fat diet began to lose their diurnal rhythm; mice normally do most of their eating and running around at night in the dark, but these ones began to eat during the day as well. “Diet- induced obesity,” report the authors of this study, “affects the control of the molecular circadian clock” (Kohsaka et al. 2007: 420). The periodicity of expres-sion of their circadian clock genes shifted on a high- fat diet, which led to “dis-organization in the feeding rhythm” (ibid.: 419). However, in further experiments, if high- fat food availability was limited to eight hours within the dark period, mice ate equivalent calories to their ad libitum – fed compatriots but did not suffer the same metabolic or circadian consequences (Hatori et al. 2012). In other words, despite eating just as much of the same high- fat diet, mice on time- restricted feed-ing regimes maintained a robust diurnal rhythm, had increased thermogenesis (body heat generation), and did not become obese or develop the unhappy condi-

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tions such as hepatic steatosis (fatty liver) and high cholesterol seen in the mice left to eat a high- fat diet ad libitum. It is difficult to compare these findings to data on humans and their refrigerators, because despite extensive work on eating habits and obesity, very little data collection on the “relationship between temporal eat-ing and obesity” has been done in humans (ibid.: 858).

In the meter of metabolism, temporality is the key property and not quantity. Function depends on synchrony, and asynchrony is disease. No one element is broken — it is a question not of mutation, blockage, or malfunction but of loss of equilibrium in the delicate balance of sleep, light, food, and body weight and per-haps even in the loss of rhythm itself. In this scheme, when the food- entrainable oscillators get out of sync with the light- and exercise- entrainable ones or, worse, rhythm is lost from the body and its environs entirely as Nature recedes into the cold blue light of a computer screen at night, “the present epidemic” arises. While a fantasy of doing without sleep altogether through some kind of pharmaceutical molecular mimicry of sleep’s effects is one strand of sleep biology, particularly for military and athletic interests, here we see the more mundane consumer- patient as the object of “basic” research into the molecular biology of the epigenetic regula-tion of metabolic genes that cycle with the circadian rhythm, overweight, under-slept, and suffering metabolic dysregulation (Wolf- Meyer 2009). A subject who hopes that weight control is sleep control and sleep control is weight control and good health is synchrony.

Scale 4: Epigenetic Encoding of the Predictive Adaptive Response

The final vignette drawn from the junction of time and food lies at a different scale, that of the nutritive milieu around the developing organism, and intergen-erational time. The theory of the “predictive adaptive response” focuses exper-imental attention on the uterine milieu of the pregnant body, in experimental animals and in humans. It crosses individual lives, connecting one generation’s ingestions to another generation’s adulthood, as well as looping single lives, see-ing early life as nascent patterning for later life. The mechanism, as in the earlier examples, relies on food as a cue or a signal, an exposure carried into the body and manifested there as gene expression potential through the molecular mecha-nisms of epigenetics (Landecker 2011). Foremost among these mechanisms is methylation, the addition of a methyl group (CH3) to the cytosine residues in the DNA sequence. Because it is readily investigated through sequencing technolo-gies, methylation has become the quantifiable sign of epigenetic change that links

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the macroscopic world of diets, wars, and social forms to the microscopic terrain of gene expression control.

For example, studies have shown results such as the following: women with low carbohydrate intake in the first trimester of pregnancy have children with altered methylation patterns in specific genes correlated with elevated adiposity at age six (Godfrey et al. 2011); children who were in utero when their mothers starved under the German blockade of Holland in the winter of 1944 – 45 show reduced methylation of genes implicated in diabetes as compared to their sib-lings born after the war (Heijmans et al. 2008); experimental mice fed a methyl- donor supplemented or depleted diet during pregnancy or very early in life show changed methylation patterns in relation to these diets, as well as changed levels of gene expression and changed physiologies (Rosenfeld 2010; Waterland et al. 2006); sheep who have had the blood flow to the pregnant uterus compromised have offspring with changed methylation, gene expression patterns, and numbers of nephrons in the kidney; male rats fed a high- fat diet produced female off-spring with altered metabolism, gene expression, and epigenetic marks, including increased liver lipid and cholesterol synthesis enzymes and reduced insulin secre-tion (Ferguson- Smith and Patti 2011) — and the list could go on.

In all of these examples, whether human or animal, food ingested at one time by one individual sets metabolic controls in another individual at another time, or the early life eating individual constitutes its own future in gene- regulatory form (Bateson 2001). The focus is on shifts in the diet of the parent, fetus, or infant in relation to the epigenetically determined closure or openness of certain stretches of the genome to transcription and translation. Methylation affects whether a gene eventually becomes “expressed” as a protein that then goes on to have a physi-ological function. Going all the way from methylation to something like nephron number in the kidney ties methylation to gene expression, and gene expression to physiological change, and physiological change to functional outcome, for exam-ple, a lowered capacity in the kidney that would make the individual more prone to high blood pressure, particularly if challenged by modern high-salt diets (Burdge et al. 2007).

Think of it as Rube Goldberg meets gene- environment interaction, where every signal causes an effect, effects often taking the form of further signals and thus transducing signals external to the body (light, touch, food) into molecular signals in the body. Far from being linear, however, each step in any signaling pathway is interlinked with many other pathways, and the capacities of any of these path-ways can be affected by the “settings” encoded epigenetically by prior experience,

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particularly during the “critical periods” of early development. In these studies, the nutritive components of the diet are understood to act in stepwise function to enter the signaling economy of the developing body, changing controls on gene expression which themselves stepwise affect functional outcomes that have the potential to persist through the life of the organism either through influencing the physical composition of an organ (cell number, tissue architecture) or through the potential for expression of genes (such as hormones) in a tissue through chro-matin structure or DNA methylation effects.

The distinctive temporality of food as information, in which exposure during development acts to set the metabolic controls by which food will be processed in the future, is nicely encapsulated in the theory of the “predictive adaptive response,” articulated most clearly by biological anthropologist Christopher W. Kuzawa (2005; Kuzawa and Quinn 2009), but also extensively in the work of Peter Gluckman and Mark Hanson in New Zealand, popularized in their book Mismatch: The Lifestyle Diseases Timebomb (2008). This theory posits that the maternal metabolic milieu educates the developing fetus as to the state of the world it will be born into. The genome, therefore, which is rather inflexible and unchanging, can be made more plastic and responsive to the environment through these molecular mediations.

One doesn’t actually need the molecular epigenetic part to have the theory of the predictive adaptive response, since the logic of it is more general than that, but epigenetics is proving a powerful mechanistic explanation for the argument that phenotypic inheritance is as plausible as genetic inheritance as a form of infor-mation transfer between generations. In animals such as voles, for example, the maternal blood concentration of the hormone melatonin and chemical by- products of grass ingestion are monitored “by the fetus as a way to calibrate maturational timing to the summer birth season,” since melatonin levels are related to day length and grass by- products are related to food availability (Kuzawa and Quinn 2009: 137). In humans, with much longer life spans, it is hypothesized that adjust-ments made by the fetus to maternal cues will confer a survival advantage in the short term, to get through gestation and early life and weaning — but perhaps won’t help or will be outright detrimental to health in the long term. Thus the idea of a “mismatch” between uterine or early life milieu, in which the nutritive milieu is encoded by epigenetic controls on gene expression, and the resulting physiology proves ill adapted to the world of plenty in which the individual lives (Gluckman and Hanson 2008). It is an adaptive response that turns out to be out of sync with the actual conditions — in this case, overabundance, sedentary life, and knowledge work, as in the above example.

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Time: Life, Mode: Signal

It may help at this point to draw these four scales together onto the same page, to see their nesting temporalities, from the momentary to the generational: singling out these four epistemic objects from the broad span of metabolic research today is not meant to suggest that they are the most important features of this land-scape; rather, they have been chosen as good illustrations of the way in which different scales of time, from the cell cycle to the life cycle, are being drawn together like loops of thread. No matter the length of thread, the loop must be closed by passing back through the eye of the needle of epigenetic control, and as the overlap point of loops of varying diameter, the tiny time of metabolic conversion is pressed up against the much larger loop of generational time — and matters to it, somehow.

That “somehow” is of course under extremely active consideration, and this is where the signal comes in. Metabolism no longer is seen as a factory whose main job is to make bodily building blocks and create energy for movement and thought but has become a zone of regulation, a space for the integration and coor-dination of external and internal signals, whose timing is as important as their nature. In the experimental and explanatory models detailed here — from glucose metabolism to parental nutrition — food is a signal whose impact persists because it ramifies through metabolism as a regulatory effect. This image of a regulatory matrix in which molecular signals connect spatial and temporal scales has arisen from a time of metabolic crisis, in which disorder arises from conflicting, asyn-chronous, or excessive signals. I have referred to the rise of these models as fat knowledge — the knowledge effects of obesity — built with experimental materials such as cells cultured in excess glucose, mice on high- fat diets, or clinical human matter in the field of cancer metabolism. However, a further step in the analysis is necessary, for it is not enough to say simply that the signal is coming to domi-nate as an explanatory term, which articulates metabolism to a discursive realm of regulation, communication, and information instead of the classic kinetic and energetic language of the enzymatic reaction. What is a signal, anyway?

Now the signal could very well constitute its own realm of investigation: it is one of the most ubiquitously used and least theorized terms in life science today. The signal is such a fundamental explanatory tool and broadly used term that those who use it do not mark its presence in any way. Reviews in the fields of biology discussed above often have obligatory overviews of subjects such as methyl- 1- metabolism or chromatin biology before moving on to the specific aims of the review, but the literature contains no overt discussion of the concept of the

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signal. The biochemistry of methylation might need to be explained, or the biol-ogy of the glucocorticoid receptor, or histone modification, but “environmental signals,” “signal transduction,” “signaling pathways,” “signaling machinery,” and the signal itself require no explanation. Research articles, which rarely define the terms used, certainly offer no reasons for the choice or use of the term signal.

In these arguments, “signaling” is often used in three senses that are conflated: first, a general sense of conveying information meant as a cue, such as the way the metabolites produced by a mother’s diet indicate to her in utero offspring what kind of environment they will be born into. The second sense refers to a signal that

Table 2 Four scales of metabolic time and space

Signal Receiver/ Thing Time Narrative Organism

Glucose ATP – citrate lyase Hours and minutes Glucose is both substrate and signal in cellular metabolism, being turned into energy in the cytosol and affecting chromatin configuration in the nucleus. Cultured cells.

Food Sirtuins Life span A class of molecules called sirtu-ins are involved in cell cycle regu-lation and metabolic response; fiddling with them in yeast and worms increases health span and perhaps (controversially) longevity.

Light, Food- Day / twenty- Rhythm in gene expression and exercise, entrainable four- hour cycle animal behavior is “entrained” by food oscillator food access that is periodic

instead of constant. Rodents.

Parental Epigenetic Conception- to- The environment of develop- nutrition encoding of death life cycle, ment, particularly the uterine the predictive intergenerational milieu, provides a set of adaptive response time “predictive adaptive signals” that

tell a developing organism about the conditions it will be born into, resetting gene expression controls perhaps for life, and perhaps for several generations, thus affecting health in old age(s). Animals, humans.

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is part of the proposed mechanism for this transmission of information — such as the molecular embodiment of fluctuations in metabolic states in the mother as a signaling molecule that can cross or be transduced across the relevant membranes. Thus dietary methyl- donor content is seen as a signal of the general nutritional condition outside the womb; it both stands for the world and directly acts on a molecular signaling pathway to enact that representation in another part of the body. The third sense refers to the epigenetic “mark” in the form of a chemical change in the chromosome — the methylated cytosine, the acetylated histone — as itself a signal, one that conveys information to other molecules in the cellular milieu.

In general terms, cell signaling denotes a large field of scientific inquiry not at all specific to metabolism. It is the study of how the body receives and acts on external stimuli, the role signals between cells and tissues play in development, how cells communicate with one another via molecular signals such as hormones and their receptors, and the internal dynamics of molecular interactions inside cells as they respond to signals of various kinds; it is a vast field of endeavor in the contemporary life sciences, with a correspondingly vast set of informational and experimental resources that were in place well before the scientific developments described here. In fact, cell signaling forms the basis for what could be described as the twenty- first- century version of cell theory. Where Rudolf Virchow once proposed that the understanding of pathology should be founded on the principle of omnis cellula e cellula — all cells come from other cells, and organisms are composed of nothing but cells — the contemporary version looks something more like this: “No cell lives in isolation. Cellular communication is a fundamental property of all cells and shapes the function and abilities of every living organism” (Lodish et al. 2000: 848).

No cell is an island, and, by extension, no cellular body may be understood apart from its channels of communication, a network both within the body and connecting to the molecular environment of the body. Signaling in biology requires its own philosophical and historical excavation — it speaks to the simul-taneous infrastructural ubiquity and ostensible banality of the concept that it has never been singled out for such study. For the purpose of this article, it must suf-fice to point out that in employing the signal, metabolic sciences are mobilizing a capacious and productive term that articulates with other expanding areas in life science such as systems biology, which is also defined by its interest in networks of molecules in interaction, and synthetic biology, which is interested in the modu-lar nature of signaling cascades and the possible engineering and reuse of those pathways to other ends (Powell and Dupré 2009). Just as the “gene” was a rather

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“floating reference,” the signal has indeterminate edges — this lack of precision does not interfere with and perhaps enhances its mobilization as a practical, bio-informatic, or conceptual entity (Rheinberger 2000; Weber 2005).

A signal, broadly understood, is a unit of communication; it may be blocked, augmented, diminished, competed with, interrupted, or mimicked. As such, it is amenable to capitalization — pharmaceutical development and intellectual prop-erty protection. The image of a discrete compound that can be taken or not, pre-scribed or bought, that stands at some important fork in the signaling pathways, is at the strategic center of how esoteric considerations of the evolutionary logic of plant molecules that interact with animal enzymes link quite immediately to prac-tical considerations of translation. The signal, then, is the hinge between inside and outside, eating and time, sugar and longevity, basic and applied, food and meaning.

The signal, with all its semiotic qualities, is today’s material zone of transla-tion, and this is where specific observations in the realm of metabolism extend readily to other biologies. Over half of all prescription drugs on the market today act by targeting G protein – linked receptors directly or indirectly (Vaquelin and von Mentzer 2008). G protein – linked cell surface receptors are pleasantly mythi-cally resonant structures, composed of a single polypeptide chain that threads back and forth across the lipid bilayer seven times, and are sometimes known as “serpentine” receptors. G protein – linked cell surface receptors receive signals; their associated G proteins transduce that signal into a form recognizable inside the cell; eventually, the signal propagates through a cascade of molecular inter-actions to reach DNA, alter transcription activity, and have physiological effect. These serpentine receptors can be activated by a whole host of molecular signals, but they form a family of similar variations that dominates the membranes of eukaryotes; 5 percent of nematode genes encode such receptors; in mice there are one thousand different, but related, serpentine receptors concerned with the sense of smell alone. According to the Molecular Biology of the Cell: “This super family of seven- pass transmembrane proteins includes rhodopsin, the light- activated pro-tein in the vertebrate eye, as well as the large number of olfactory receptors in the vertebrate nose. Other family members are found in unicellular organisms; the receptors in yeasts that recognize secreted mating factors are an example. In fact, it is thought that the G- protein- linked receptors that mediate cell- cell signaling in multicellular organisms evolved from sensory receptors that were possessed by their unicellular eukaryotic ancestors” (Alberts et al. 1998: 493).

In short, a very large number of genes in animal genomes (including humans)

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are committed to producing receptors and their linked proteins that receive molec-ular signals from the outside of the cell and convert them into a series of molecular events inside the cell. It is perhaps not surprising that organisms commit so much of their substance to becoming an interface between an inside and an outside, but this biology of the in- between, which has been articulated in the language of signals since the mid- 1960s, has remained extremely muted in models of life to date. After a brief flourishing in the 1970s of the idea of hormones and neurotrans-mitters having evolved from metabolites — the metabolic origin of thought — such interactive models of life sank back into themselves as biologists flocked to find out the genetic basis for hormone action or the signaling cascades associated with oncogenes (Tomkins 1975). Today the theoretical and practical significance of the signal is resurgent; it provides a conceptual, technical, and now economic transla-tional link between environments and organisms, between one time and another, and between the scale of DNA and cells and the scale of organisms and societies.

Conclusion: The Long and Short of It

In 1931 the socialist biologist J. B. S. Haldane declared, “The ultimate aim of bio-chemists may be stated as a complete account of intermediary metabolism, that is to say, of the transformations undergone by matter in passing through organisms” (1931: 1). Today we see something of a reversal in this formulation, as life sci-ence begins to focus on the transformations undergone by organisms in passing through matter. Instead of flowing through the body, expelled as heat and waste, so- called foreign matter is assimilated to help the body live not in but into an environment in its future, to anticipate, to be preemptively defensive, to thrive on stress. Sometimes this is advantageous, sometimes deleterious, particularly when organisms have to pass through a material world not of nature but of industrial effluent and industrialized eating.

The biological research described above is simultaneously a philosophical and eminently practical shift in the matters of time, sleep, eating, and fat. Whereas nutrition science emerged in an era of scarcity and grew in legitimacy and scope through the investigation of deficiency diseases and the body’s ability to generate and store energy from food, today metabolic science is characterized by its drive to understand the biology of excess, of hyperphagia, of overload. As mundane as it may seem, the prevalence of fat bodies in Western societies has brought different clinical and agricultural matter — different tissues with different problems — into focus, specifically fat. Even the standard control rodents in American laboratories, the relatum to which experimental difference is meant to register, have become

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metabolically morbid (Martin et al. 2010). Agronomists who a hundred years ago might have been charged with making food animals grow fatter more quickly now attempt to make animals that satisfy “the demand for meat animals of low carcass fat to meet nutritional recommendations for a reduction in dietary lipid intake, particularly of saturated fatty acids”; at the same time, biomedical researchers seek their own therapeutic answers to human fat, which for most of the twentieth century was regarded as an inert substance with a storage and insulating function: “Interest in the biology of white adipose tissue has risen markedly with the recent surge in obesity and its associated disorders. The tissue is no longer viewed simply as a vehicle for lipid storage; instead, it is recognized as a major endocrine and secretory organ” (Trayhurn and Bing 2006: 1237).

White fat cells are now understood to secrete a wide range of signaling mole-cules that modulate inflammation, appetite, and fat metabolism, and many of these molecules are produced within adipose tissue’s distinctive circadian rhythms. “Shift work, sleep deprivation, and exposure to bright light at night have been shown to be related to increased adiposity and prevalence of MetS [metabolic syndrome]”: this epidemiological observation of the world of work then moti-vates practical investigations at the cell and the molecular level. Subcutaneous and visceral fat tissue explants obtained from severely obese women undergoing bariatric surgery and kept in culture showed rhythmic expression of circadian clock genes for two days after excision from the body (Gómez- Santos et al. 2009: 1481). Fat sleeps and wakes, cycles, expresses, signals; arrhythmicity and excess come together.

Postindustrial metabolism, as I have argued, both comes after and is very materially and literally produced by industrial metabolism. In many ways, the fat knowledge whose production is explored here might be understood as the biol-ogy of risk society, in this case focused on metabolic risks. Value arises not in the conversion of raw materials to manufactured goods, and the further exchange of goods in society in which one kind of value is converted into another, but in the amelioration of the fattening effects of industrialization, in the treatment of the metabolic ills of knowledge economies, in the extraction and concentration of the effects of evolution to treat the maladapted citizen of the technological environment.

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