I am greatly honored to have my name associated with Jonathan E. Rhoads and with the American Society for Parenteral and Enteral Nutrition (A.S.PE.N). The name Jonathan E. Rhoads connotes excellence in academic surgery and pioneering work in parenteral nutrition. The basic work of surgery, parenteral nutrition, and indeed all of medicine is doing something beneficial for the body that it cannot do for itself. This is a concept generally associated with government, which is supposed to do something for the people that they cannot do for themselves. Government sometimes succeeds, and in medicine and surgery we sometimes succeed. The story of nutrition is one of the great successes. In the early part of this century, the dietary ingredients needed for good health were sought and found. The success story of parenteral nutrition is more complex, because the nutritional needs of the injured and severely ill require delicate tuning of nutrients, electrolytes, water, and gases. Nevertheless, parenteral alimentation in the great tradition of clinical nutrition attends to the special needs of the sick body by doing for it what it cannot do for itself. I will argue that our interventions on behalf of the obese patient deal with physiological considerations even more complex than those that underlie the scientific practice of parenteral alimentation, but that these interventions are a valid extension of nutrition science, even as parenteral alimentation was an extension of the nutrition science of an earlier period. I will emphasize that there remains a lot of unfinished business in obesity research.
During World War II and afterwards, it became increasingly evident that the tragic consequences of war had paradoxically conferred some benefits to those who had suffered hunger and weight loss. There was evidence for a temporary abatement of the ravages of diabetes, hypertension, and arteriosclerosis. It was reasoned that even an unhappy disengagement from all of the good things of life that had come to us since the beginning of the industrial revolution might lessen the severity or prevalence of some illnesses. We now realize that as steam and internal combustion engines replaced the need for human and animal adenosine triphosphate (ATP) in the performance of work, and also as a great abundance and variety of foods were made available to us, we changed not only our patterns of physical activity and nutrition but also the diseases from which we suffer. The "thrifty" genes and the basic biochemical apparatus for coping with a low energy input in the face of the need to perform work, which is that collection of proteins for which the thrifty genes code, were made redundant by the benefits of the energy-rich environment of the western world. It is widely accepted that this state of affairs is at the core of the problem of obesity as well as diabetes, arteriosclerosis, and other disorders of modern humans. The proof often cited is the decline in these diseases during the great wars in the middle of our century as well as the low prevalence of these diseases in the nonwesternized part of the world that has not yet tasted the benefits of our industrial revolution.
With this understanding, the cure for the new diseases of the western world should be readily at hand: nothing more than a return to an earlier life style. This suggested cure is implicit in many currently popular and important programs for increasing physical activity, lowering caloric intake, and learning new ways to "cope" with stress. It should work. Eating less when there is lots of food should be infinitely easier than eating more when food is scarce; but it has not worked. During recent decades, this explanation for obesity along with vivid warnings as to the hazards of obesity has been given to the public in much the terms that I have outlined, yet the prevalence and severity of obesity have continued to rise. We feel guilt about our lives of overindulgence and wonder whether obesity is in some measure a manifestation of willfulness or hedonism. Such moralizing is not helpful and is not our province. Our role, as nutrition scientists, is to take a less "vitalistic" stance and to examine the possibility that scientific understanding of how the body deals with the intake and outgo of energy will give us the tools needed for treating and preventing obesity.
The modern period of research in energy metabolism began roughly 200 years ago when Lavoisier examined the relationship of animal heat to oxygen consumption and carbon dioxide production. He made it clear that respiration and oxidation within the body are fundamentally the same process as the combustion of inert materials. From these studies, it became possible to apply the laws of conservation of energy to living systems (ig. 1). Let us consider that the essential components of the energy metabolic system in animals consists of the following: (1) an intake system for energy (Q) acquisition, (2) a system of combustion in which energy (W) is converted into work and heat and finally, (3) a locus for energy storage (E), namely, adipose tissue. The exact control mechanism for the level of energy storage was not clarified by Lavoisier's work, and thus the nature of obesity, an unwanted increase in energy storage, remained obscure. But the applicability of the first law of thermodynamics, AE = Q - W, is certain. The amount of energy stored changes only when there is an inequality of intake and outgo.
Early in this century, it was thought that the regulation maintaining constant energy storage might reside in the ability of the metabolic compartment to burn more or fewer calories at different rates to assure constant energy storage. Excess consumption of calories was countered by "Luxus Konsumption," the burning away of extra calories, thereby avoiding excess fat storage. An error in the operation of this system might therefore lead to obesity. This once popular idea was resurrected when it was realized that brown adipose tissue is a thermogenic organ and some animals have the ability to generate heat in a process of nonshivering thermogenesis in which ATP utilization is uncoupled from useful metabolic work or physical activity. The likelihood that Luxus Konsumption, or for that matter brown adipose tissue, plays an important role in caloric balance in humans was dealt a nearly fatal blow by the classic work of L. H. Newburgh and his associates,' published more than 65 years ago. In extremely careful metabolic studies, Newburgh could find no evidence for low dissipation of energy by obese subjects. He showed that body weight measurements could sometimes be difficult to interpret because of prolonged periods of water retention or other compartmental shifts, but energy conservation applies to obese subjects in exactly the same way as it does to the nonobese. There are no unanticipated differences in energy expenditure in obese subjects when compared with the nonobese. He therefore concluded that it is food intake rather than energy expenditure that is the "error" that causes obesity. Causes for the increased food intake were thought to be largely in the psychological realm, and thus the post-Newburgh period until the late 1960s was one of focus on behavioral or psychological work in obesity research. Figure 2 highlights the central role of food intake as the hypothesized regulator that determines whether or not there will be an alteration in fat storage. Previous workers had shown that the laws of conservation of energy applied to humans, but Newburgh showed it applied to obese humans as well.
The primacy of psychological or behavioral factors implicit in the Newburgh model of obesity found widespread acknowledgement and acceptance. At that time, a wave of behavioral and dynamic psychiatry flooded into theoretical considerations of disease causation. Beginning in the late 1920s, studies of the pathogenesis of hypertension, peptic ulcer, asthma, and a variety of illnesses examined a "psychosomatic" approach. In this model of disease, behavior and personality were central, mediating between environmental conditions and body needs. Clinical observations of obese subjects appeared to fit just that model.
In 1942, Hetherington and Ranson2 showed that a model of human obesity could be produced in the rat by electrolytic lesions of the hypothalamus (Fig. 3). This was not a total surprise because clinicians had implicated the hypothalamus in a syndrome of early-onset obesity and delayed sexual behavior, termed Frohlich's syndrome. Also, the late effects of the post-World War I epidemic of encephalitis lethargica included cases of sudden onset of obesity believed to be related to virally mediated hypothalamic damage. The clear demonstration that hypothalamic obesity could be produced experimentally enlarged the models proposed for the control of energy metabolism. Other animal models were established by chemical lesioning of the hypothalamus, and also new models of genetically determined obesity were found in mice and rats. In retrospect, it is not surprising that rodents were a rich source of "genetic" obesity. No other vertebrate strain had lived so close to humans, dependent upon humans for food, but unlike pets or domestic animals, widely hated and reviled as pests. A notable exception is the oriental mouse "fancy." Mice were bred to be fat and yellow or have other "endearing" characteristics. In other societies, mice and rats were not treated so gently. If intermittent starvation can be an evolutionary force selecting for mutant genes that are "thrifty," then rodent denizens of barns and garbage dumps, sometimes full and often empty, might be just the animals to segregate such genes. A period of increasing investigation of animal models and humans using newly developed methods of biochemistry and endocrinology began in the 1950s. A special virtue of the Hetherington-Ranson finding was to give heart to all those who sought additional understanding of energy metabolism outside of the behavioral realm.
I became interested in energy metabolism about 40 years ago when my colleagues and I wanted to learn more about the role of adipose tissue in lipid metabolism in humans. Initially, it was thought that adipose tissue was simply an insulator and an inert energy storage tissue. However, the work of many had indicated that active metabolism was occurring in the narrow rim of cytoplasm surrounding the fat storage droplet of the adipocyte. As we studied the cellularity of the tissue, it became evident that the reducedobese human subject was not like the never-obese subject. There were more adipose cells of small size in the reduced obese. This finding, more than any, led us to search for a role of adipose tissue in the control of energy metabolism and suggested that the errors that created obesity might be found not only in the psychological or hypothalamic realms, but in other tissues as well (Fig. 4). More recently, studies performed in collaboration with Rudolph Leibel and Michael Rosenbaum2 have shown that experimentally produced alterations in body weight in humans can produce profound changes in energy metabolism. Our work suggests that alterations in the mass of adipose tissue leads secondarily to alterations in energy metabolism by mechanisms yet to be understood. But a chemical description of how the adipocyte might be involved in the control of energy metabolism awaited the new techniques of molecular genetics.
The genetic obesity of rodents never ceased to be of interest to obesity researchers. It was obvious that genetic aberrations in energy metabolism constituted a rich vein to be mined in the search for regulators of energy metabolism. New methods of gene cloning have proven this to be true. Genetically obese rodents have been found to have a variety of defects.4 Most recently, a mutation of the gene for melanocortin-4 receptor has been implicated in the obesity of the yellow mouse. Among the various genetic lesions in obese animals is a defect that leads to the inability to elaborate or secrete an adipocyte-derived peptide, termed leptin. This is the molecular genetic explanation for obesity in the ob/ob mouse. A failure for the "signal" from the adipocyte to be detected by the central nervous system (CNS) has been found to be cause of other obesities, namely, the db obesity of mice and Zucker rat obesity. These observations have given a chemical basis to the conjecture that adipose tissue is not only a storage depot for calories, but also a locus for the control of energy metabolism (Fig. 5).
The sudden development of a repertoire of chemical signals involved in energy metabolism has led to a flurry of activity examining the role of such peptides as neuropeptide Y, insulin, melanocyte-stimulating hormone (MSH), and others in human and animal obesities. One can expect a rich harvest of new information to come from these endeavors within the next few years.
There are at least two questions which remain unanswered and are not likely to be answered by current research directions, thereby suggesting that the unfinished business of obesity is not only application or translation of present molecular findings, but also searches in new directions.
The ultimate regulators of energy metabolism in humans are the decisions to eat or not and to exercise or not. These are behaviors that we have already considered from a psychosocial viewpoint in previous models. Our earlier endeavors to understand energy metabolism as governed by behavior were not fruitful in generating useful new knowledge nor were they helpful in treatment of obese subjects. Now behavior reenters the model as an extension of genes and proteins. What is the nature of the chemical or neural signals that directly affect the decisionmaking apparatus in the brain that is the proximate neural determinate of these behaviors? There is a wide gap between peptides and people.
How do environmental factors such as plentiful food and the opportunity to be indolent induce a seemingly irreversible state, such that as each step of obesity is achieved, the energy regulatory system acts to oppose a decline to more healthful levels of body weight? How does this ratcheting upward of fat storage come about?
I cannot answer either question, but some experimental findings suggest that answers may be forthcoming. Searching for links from peptides to behavior suggests a need to find arms of the energy regulatory system that might incorporate the highest levels of CNS function. It is worth noting that changes in fat storage can alter regulatory systems such as the autonomic nervous system, which is widely distributed in the body and thus affects the function of many organs.5,6 The parasympathetic branch of the autonomic nervous system is one particular system, although the sympathetic branch has more often been studied because its activity can be monitored by measuring catecholamines in blood. There are marked changes in parasympathetic activity with weight variation. With induced increases in body weight in humans, parasympathetic activity declines, and with weight reduction, parasympathetic activity rises. Are there other systems with such widespread organ innervation as the parasympathetic nervous system that might affect behavior? Is it possible that the alteration of parasympathetic activity itself is important in CNS function? How peptides and hypothalamic activity affect human behavior will be an important issue for future research.
Now, to the second question concerning the ratcheting upward of fat accumulation. The readiness with which we have succumbed to the plenty of western living by developing increased fat storage in obesity is phenomenal. But the inability to recognize these events and act to reverse obesity by doing the obvious, eating less and exercising more, is even more phenomenal. The force that attracts fat to us seems greater than the forces that can pull it away. Animal studies have shown that genetically ordained body size and shape can be permanently affected by nutrition manipulations in the earliest days of life. Whether there are special times of sensitivity to the environment that alter development of the energy control system can only be conjectured at this time. New research will look to developmental effects on gene expression. The exploration of environmental influence on animals with defined genetic makeup is likely to be very rewarding. Could the freedom from childhood diseases along with abundance of food and leisure time be involved? Are there other environmental determinants of energy storage not yet considered?
The histological observation that brought me into a search for the biological basis of human obesity needs revisitation. Obese subjects make and maintain more and larger fat cells than do nonobese subjects. New data on tissue factors that control the fibroblast to adipocyte conversion could be central in future obesity research.3 Can altered nutrition expand the adipose cellular bed in such ways as to have irreversible changes in the storage bed of energy, acting to drive in body weight upward?
Thus the frontiers for obesity research may be wider than probing more deeply into the molecular genetics of each cell, productive as that may be. The future holds the possibility for new ways of examining the integrative control of energy metabolism, such that behavioral and developmental factors are considered. The model of energy regulation will then be as shown in Figure 6. A return to integrative physiology that incorporates behavior and development is our hope for 2000 and beyond.
Newburgh LH, Johnston MW: Endogenous obesity-a misconception. Ann Intern Med 3:815, 1930
Hetherington AW, Ransom SW: Spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol 136:609-617, 1942 Leibel RL, Rosenbaum M, Hirsch J: Changes in energy expenditure resulting from altered body weight. N Engl J Med 332:621-628, 1995 Spiegelman BM, Flier JS: Adipogenesis and obesity: Rounding out the big picture. Cell 87:377-389, 1996
Hirsch J, Leibel RL, Mackintosh R, et al: Heart rate variability as a measure of autonomic function during weight change in humans. Am J Physiol 261:R1418-1423, 1991
Aronne LJ, Mackintosh R, Rosenbaum M, et al: Autonomic nervous system activity in weight gain and weight loss. Am J Physiol 38:R222225,1995
JULES HIRSCH, MD
The Rockefeller University, New York
Received for publication, February 21, 1997. Accepted for publication, March 11, 1997.
Correspondence: Jules Hirsch, MD, The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399.
Copyright American Society for Parenteral and Enteral Nutrition Jul/Aug 1997
Provided by ProQuest Information and Learning Company. All rights Reserved