John Brobeck, and the Hypothalamic Control of Eating (I)
BROBECK, J. R., TEPPERMAN, J., and LONG, C. N. H. Experimental hypothalamic hyperphagia in the albino rat. Yale Journal of Biology and Medicine 15: 831-853, 1943.
Comment by Harry R. Kissileff, St. Luke’s/Roosevelt Hospital and Columbia University
I chose this classic because it was the first paper to show definitively a causal relationship between a purely ingestive behavioral response and a brain manipulation. Specifically, overeating was shown to be the primary cause of obesity in rats with ventromedial hypothalamic lesions. As such, this paper could be considered the granddaddy of all papers in the neuroscience of ingestive behavior. Before this paper, there were numerous clinical studies, preliminary reports and arguments, as there have been since then, about how important excessive food intake was for the obesity that ensued from these lesions. For example, Hetherington and Ranson (13), who had seen excessive food intake in some rats, apparently made lesions in a slightly different part of the brain (they did not report their histology in detail, but referred to a prior paper). However, they missed the phenomenon because they did not really think food intake was the important factor. As they note in their paper: “When the simultaneous reports of preliminary work by Tepperman, Brobeck and Long (1941) and Hetherington (1941) appeared, the former group (who had done little or no work on activity) emphasized the high food intake of their animals; whereas the latter was more impressed by the tremendously decreased activity of the obese rats. Insistence upon the primary importance of either viewpoint would in all probability represent over-simplification of the problem.” (p. 615). For further information on the importance of this paper and background in relation to its time and the 30 years that followed see Smith’s excellent review. (24)
The key finding is that Brobeck and colleagues showed for the first time that damage to a part of the brain results in a significant change in ingestive behavior, namely overeating. Without this essential demonstration, the neuroscience of ingestive behavior might have been delayed for years. One of the less well known aspects of this finding is how it was discovered, as was detailed by Brobeck (7) in his address to the Society for the Study of Ingestive Behavior as the first recipient of its distinguished career award, in 1992. At the time of the work he was a second year medical student at Yale, having already received his Ph.D. from Northwestern in 1939. He wrote there as follows:
In a few months I reported to Dr Long that I thought I was ready to operate upon his precious diabetic animals, because I had made hypothalamic lesions in replication of Hetherington’s work (Hetherington and Ranson, 1940), and found that my rats were getting fat. So I was confident that I could place hypothalamic lesions. Dr Long’s response, however, surprised me. Instead of saying, “Great! Let’s get on with the diabetic rats,” he said “They’re getting fat? What are they eating?”
The point of this story is that Brobeck, in 1943, did not have a grand theory of hypothalamic function that was being put to the test. He was simply trying to replicate a previous result in order to advance to the next stage. His supervisor had the good sense to ask the right question. However, coupled with the next Ingestive Classic (Anand and Brobeck, 1951; comment by Timothy H. Moran), it became the basis for the central dogma that still dominates the field, namely that there are inhibitory and excitatory systems (back then they were “centers” but the concept is the same) in the brain that control eating behavior and body weight. Before Brobeck, hyperphagia had been seen in monkeys and dogs, and even rats, but showing it was the cause of obesity in rats made it possible for the next generation to explore the phenomenon. Before this work became the basis for the “central dogma”, peripheral theories, such as Cannon’s gastric contraction hypothesis were the basis for hunger, which generated eating. Eating put a stop to the contractions. Satiation wasn’t really on the map. The idea that eating started and stopped in response to signals was driven by notions of peripheral on and off hunger signaling. Other possible signals for stopping the meal received little attention, despite Richter’s (20) demonstration of “meal eating” in rats (see also (24)).
The classic paper demonstrated the primacy of food intake as a causal mechanism in several different ways, which are still instructive from the standpoint of logical application of scientific method.
First, they showed that the change in eating occurred within minutes after the anesthetic wore off: “Hypothalamic lesions which eventually induced adiposity were found to produce an increase in the amount of food eaten by the rat - an increase which was usually evident even before the animal had completely recovered from the operation.” (p. 834). Thirty years later, in my own laboratory (4), I had the pleasure of documenting this finding, by recording the spontaneous pattern of eating in rats with previously implanted indwelling electrodes that required only light anesthesia to place the electrolytic lesion. As shown in the Figure 1, the overeating was remarkable in its immediacy.
Second, they showed that there was a significant correlation between food intake and weight gain, thereby demonstrating that food intake was sufficient to explain the observed weight gain (see Figure 2).
Third, they showed that the overeating was necessary to obtain the weight gain. While others have shown that various blockades (e.g. vagotomy, diabetes, unpalatable foods, can prevent obesity caused by overeating, none of this, can refute the fact that simple food restriction, i.e. pair feeding to a control, or complete starvation prevented weight gain, in most of the affected animals. Furthermore: “When they were fed normal quantities of food, they frequently ate a 24-hour portion within a few hours” (p. 851).
Fourth, they accounted for the findings of others, namely that there were metabolic effects. They found decreased oxygen consumption as well as decreased activity. However, they demonstrated that these were secondary to the increased food intake because: “During self-selection feeding experiments and during complete fasting the animals were evidently able to use fat as a source of energy. Their fasting oxygen consumption was the same as that of control rats of comparable weight” (p. 851).
Fifth, they did not shy away from reporting salient observations from individual animals. Exemplary studies with single animals have introduced important new phenomena in the past, e.g (3).
Sixth, they showed that that the overeating subsided when the animals reached a high weight level. They described the dynamic and static phases of the phenomenon that later gave rise to the set point theory (15)
Another reason I feel this paper is a classic is that the findings reported had ramifications far beyond its original audience of physiologists and endocrinologists. Although it has currently 529 citations on Google Scholar, it was republished in a collection called “Animal Drives”, in 1965 (8), in the company of several other papers that dealt with various aspects of motivation and reward. It was the basis for Stellar's 1954 paper on motivation (25), Neal Miller et al.’s classic demonstration of lack of motivation in these animals (18), and effects of hypothalamic knife cuts between the VMH and lateral hypothalamus (LH) (12),(23). It inspired the search for glucoreceptors (see Ingestive Classics by Jean Mayer and Barry Levin’s comment), and electrophysiological recording from nerve cells in the ventromedial hypothalamus (19) in search of receptors for metabolites as well Epstein's chemical injection work with the anesthetic procaine, which caused an acute and reversible chemical inhibition of the cells (10). It was the driving force behind an influential theory of obesity in humans developed by Stanley Schachter (21). It inspired early work on the effects of both electrical (9) and chemical stimulation (26) which could enhance or inhibit behavior. It became the focus of work on the importance of anatomical connections to other pathways in the brain, and for current concepts of the role of feedback from adipose tissue and metabolites in the control of ingestive behavior (16) (1),(17).
One of the most controversial aspects of Brobeck et al.’s paper is whether VMH lesion-induced obesity is really driven by food intake or whether the food intake is secondary to a metabolic disturbance. After investigating this issue almost 40 years later by means of knife cuts, Bray, Sclafani and Novin (6), and Sclafani (22) concluded that hyperinsulinemia may be independent of hyperphagia. On the other hand, the obesity does seem to depend on hyperinsulinemia, as it is blocked by operations that prevent it, such as vagotomy. Although the hyperinsulinemia appears to be a primary effect of the lesion, there is no evidence that it contributes to the hyperphagia in any way. Berthoud and Jeanrenaud (5) showed what I think is the best evidence for independent hyperinsulinemia caused by the lesion. They found that insulin release occurred immediately after the lesion. In lesioned, as opposed to control rats (cortically but not hypothalamically lesioned), insulin continued to rise and was blocked by vagotomy. It is therefore reasonable to conclude that disinhibition of feeding and stimulation of insulin release are independent. The excessive insulin release results in deposition of the excess energy as adipose tissue. However, there is no evidence that the hyperinsulinemia drives food intake.
A second major paradox, that now seems resolved, regarding the notion that the VMH lesion inhibits the lateral hypothalamic driver of feeding and thus initiates satiation, is that attempts to show deficiencies in the classic satiation pathways, namely gastric distension induced by saline or water infusions, nutrients in the digestive tract (27), and infusion of hormones that induce satiation (11) have all worked normally in rats with VMH lesions. However, the fact that the hyperphagia abates when the animals become obese, prompted Hoebel and Teitelbaum (14) to propose “some stimulus correlated with obesity controls food intake, probably by activating cells in the ventromedial hypothalamus” (p. 193). In the intervening years this stimulus was proposed to be insulin and later leptin (see (28) for recent review). It therefore appears that despite the inference that lack of response to short-term satiation signals triggered hyperphagia in the VMH lesioned rat, it now appears that the lack of satiation is the result of removal of a tonic long-acting signal.
Personal reflections: I was privileged to work with John Brobeck as my “teaching coach” during my first appointment as an assistant professor at the University of Pennsylvania, School of Allied Medical Professions, where I taught physiology for five years (1971-1976). During that time, Emil Becker was my graduate student, and we wrote up the studies I mentioned above, which had been done at the Rockefeller University, and followed them up with several more on circadian rhythms and other aspects of meal pattern analysis in rats with VMH lesions and pregnancy and lactation (E. Becker, unpublished, doctoral dissertation, CCNY, Hunter College). While I was an undergraduate and graduate student at the University of Pennsylvania, under the mentorship of Alan N. Epstein, I was taught the importance of “getting a phenomenon”. In those days research (at least in the lab I worked in) was driven mainly by what you found, not necessarily by how it was interpreted or what theory you used. It is remarkable that the field of ingestive behavior, as I see it, began with a phenomenon, the overeating in rats with ventromedial hypothalamic lesions. There was no grand theory of neuro-circuitry, transmitters, nuclei and pathways, just the finding that a big hole in a specific part of the brain caused overeating. My own research was similarly driven in the early days by phenomenology. However, what made Brobeck’s work compelling and important in subsequent years was the development of a theory. As Moran describes in his comment on the Ingestive Classics paper of Anand and Brobeck (2), it was the finding of an opposing lesion in an adjacent part of the brain that led to what is now a relatively oversimplified theory of eating behavior, based on the “hypothalamization,” to coin a term, of the Sherringtonian reflex arc with inhibitory and excitatory controls. So I end with a plea that young scientists should be given the chance to find phenomena, before they are forced to develop theories, but that theories must inevitably be developed for progress to be made.
Acknowledgements: I thank Anthony Sclafani and Gerard P Smith for providing some of the material referred to in this commentary, and Barry Levin for editorial corrections. I thank Nori Geary for keeping me on track about the insulin story and the “hypothalamization” of Sherrington.
Figure 1. Graphic replication of Brobeck Tepperman and Long (1943). Four daily meal-pattern plots of a liquid diet from a rat before and after ventromedial hypothalamic lesion from previously implanted electrodes. The trace shows food intake across time, with intake in ml computed from lick/intake ratios. Lesions were made on day 1 (third line of record). Note that lesions immediately induced a large meal. Body weights are shown on the right (extracted and replotted from (4)).
Figure 2 – Taken from the classic paper.
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