Gordon C. Kennedy and the Lipostatic Control of Eating
KENNEDY, Gordon C.
The Role of Depot Fat in the Hypothalamic Control of Food Intake in the Rat. Proc R Soc B Biol Sci 1953;140:578–592.
Comments by David Levitsky, Cornell University (September, 2016)
Few researchers have had a greater impact on our theoretical understanding of the control of food intake and regulation of body weight than Gordon Kennedy. In a few simple, but elegant, studies sometimes using only a handful of animals, he revolutionized the science of eating and laid the theoretical foundation for contemporary research in the control of body weight. In this classic, “The role of depot fat in the hypothalamic control of food intake in the rat”(1), he proposed that the critical effect of ventromedial hypothalamic (VMH) lesions that led to obesity was destruction of chemoreceptors that were sensitive to metabolites released from the fat depots. Eating was a behavioral mechanism responsible for maintaining constant the total amount of fat in these depots, a process Kennedy named “lipostasis.” This was a radical departure from the conventional idea at the time that the hypothalamus simply turned on and off eating behavior.
The concept of specific “feeding” and “satiety” centers in the brain emerged from the explosion of neurological studies of the hypothalamus following Brobeck’s pioneering discoveries (see Ingestive classics # 5 and 6 (2,3)) . The crucial question debated at that time was not whether feeding and satiety centers existed, but rather the nature of the peripheral signal that communicated information from the periphery to these important feeding centers? There were two major positions. On the one side, Jean Mayer argued that the amount (utilization) of circulating glucose was the signal (Ingestive classics #1 (4)). On the other side, John Brobeck argued that eating was controlled by thermoreceptors, which would stimulate eating in cold environments and inhibit eating in warm environments or after meals, when the thermic effect of food increased body temperature.
Kennedy’s 1953 paper described several tests of Brobeck’s position. If the signal to eat or not to eat was based on hypothalamic temperature, then hypothalamic damage that resulted in hyperphagia and fat accumulation should disrupt the relationship between ambient temperature and food intake. To test this hypothesis, he housed small groups of VMH-lesioned rats (n = 4) and intact animals in rooms having either normal or high ambient temperatures. Observing a large effect with a small number of animals was important to demonstrate the profundity of the manipulations. He observed that the lesioned animals inhibited their intake in the heated room to the same degree as the intact rats and lost about the same amount of weight. He then reduced the weight of hyperphagic animals to their pre-operative values by food restriction and then gave them ad libitum access to the food. The hyperphagia that was evident after the initial surgery re-appeared both at normal ambient temperature and at higher temperature. These results clearly challenged Brobeck’s theory because, if the overeating was caused by the destruction of hypothalamic thermoreceptors, the relationship between ambient temperature and food intake should have been altered.
He also reported a study using only two VMH lesioned rats and one littermate control in which he subjected the animals to a diet consisting of 50% chow and 50% kaolin. He observed that both VMH-lesioned animals decreased their food intake and lost weight, while the control animal was minimally affected. Then, when returned to the 100% chow diet, the intakes of the VMH-lesioned animals doubled and their body weights returned to their post-lesion level, while the control rat was relatively unaffected. He had published a paper two years earlier (5) in which he observed that older, fatter, rats showed a sharp decline in intake on kaolin adulteration of the diet, whereas younger, less obese rats showed little change in their body weight. These earlier findings, combined with the results reported in this paper, laid the foundation for Kennedy’s idea that it was not the on/off switch for eating behavior that was being disturbed by hypothalamic lesions, but rather the regulation of total body fat. Indeed, Kennedy coined the term “lipostasis” to refer to the process whereby body fat was regulated through the control of food intake and energy expenditure.
One of the first feeding researchers to pick-up the significance of Kennedy’s revolutionary thinking was Jean Mayer. Although much of his famous 1955 paper to the New York Academy of Sciences (6), was dedicated to his glucostatic theory, he cited Kennedy’s “hypothesis” that regulation of body fat was the basis of long-term regulation of body weight, while his glucostatic theory was more related to short term, meal-to-meal regulation.
Twenty-two years later, Richard Keesey and Terry Powley (7), working primarily with animals subject to lesions of the lateral hypothalamic area, explicitly applied the concepts of control theory, in particular the “set-point” concept, to Kennedy’s idea of body fat being regulated by hypothalamic structures.
Kennedy’s concept of the regulation of body fat and Powley and Keesey’s use of the term “set-point” revolutionized the way we considered eating behavior and obesity. Most importantly, it shifted attention from short-term circulating metabolites that might signal the stimulation and termination of eating behavior to the search for signals that enable the regulation of adiposity. This search famously resulted with the discovery of leptin (8), a hormone that is produced by adipocytes that is released into the circulation in proportion to the adipose tissue mass, and that stimulates receptors in the hypothalamus (and other brain areas) that control energy intake and expenditure.
By the turn of this century, the set-point theory of the regulation of body weight was considered such a complete story, explaining everything from neuroanatomical pathways to why it is so difficult for people to maintain weight loss following dietary restriction, that most neurobiological researchers in the field seemed to ignore the accumulating evidence for the role played by environmental stimuli to the control of food intake.
About the time of the discovery of leptin, there was increasing recognition of the severity of the worldwide obesity epidemic and increasing pressure from the public health sector to find safe and effective methods to treat or prevent overweight and obesity. Although research on regulation of adipose tissue has stimulated hundreds of publications documenting the involvement of the putative set point in the regulation of energy homeostasis, it failed to provide an effective solution to the problem of the epidemic of obesity. This desperate need to find a solution to the obesity problem fostered a shift from a focus on the purely “homeostatic” mechanisms that control food intake to “non-homeostatic” mechanisms that control food intake, notably including environmental influences and flavor hedonics (9).
Regardless of which theory eventually prevails, Kennedy himself will remain a model of how a scholar can, with deep thinking and simple experiments, make fundamental contributions to an area as complex as energy balance. Kennedy was one of those rare “revolutionary heroes” described by Kuhn in his book, The Structure of Scientific Revolution (10), who has changed the way we think.
2. Kissileff HR. John Brobeck, and the Hypothalamic Control of Eating (I) [Internet]. Society for the Study of Ingestive Behavior. ernet]. 1994;372:425–32. Available from: http://www.ssib.org/web/classic5.php
3. Moran TH. Bal Anand and John Brobeck and the Hypothalamic Control of Eating (II). Ingestive Classic 6, Society for the Study of Ingestive Behavior. ernet]. 1994;372:425–32. Available from: http://www.ssib.org/web/classic6.php
4. Levin BE. Mayer and the Glucostatic Hypothesis. Ingestive Classic 1, Society for the Study of Ingestive Behavior. ernet]. 1994;372:425–32. Available from: http://www.ssib.org/web/classic1.php
5. Kennedy GC. The hypothalamic control of food intake in rats. Proc R Soc London B Biol Sci. The Royal Society; 1950;137:535–49.
6. Mayer J. Regulation of energy intake and the body weight: The glucostatic theory and lipostatic hypothesis. Ann N Y Acad Sci [Internet]. 1955 [cited 2016 Jul 26];63:15–43. Available from: http://doi.wiley.com/10.1111/j.1749-6632.1955.tb36543.x
7. Keesey RE, Powley TL. Hypothalamic Regulation of Body Weight: Experiments suggest that the lateral and ventromedial hypothalamus jointly determine the regulation level or“ set point” for body fat. Am Sci. JSTOR; 1975;63:558–65.
8. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature [Internet]. 1994;372:425–32. Available from: http://dx.doi.org/10.1038/372425a0
9. Lutter M, Nestler EJ. Homeostatic and Hedonic Signals Interact in the Regulation of Food Intake. J Nutr [Internet]. 2009;139:629–32. Available from: http://jn.nutrition.org/content/139/3/629.short\nhttp://jn.nutrition.org/cgi/doi/10.3945/jn.108.097618
10. Kuhn T. The structure of scientific revolutions. Chicago IL, USA: University of Chicago Press, 1962; 4th ed., 1972. ;