Porte and Woods and Insulin as an Adiposity Signal
WOODS, S.C., E.C. LOTTER, L.D. McKAY, and D. PORTE, Jr.
Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282: 503-505, 1979.
Comment by Stephen C. Woods (04/27/16)
In 1953 Kennedy proposed the so-called lipostatic theory, stating that the amount of fat in the body is regulated, and that variations of food intake are important contributors to the regulatory process . A key unanswered question concerned how brain areas controlling food intake are coupled to information about body fat content. Prevailing hypotheses in the 1960s and 1970s were based on the idea that fat mass affected the availability of metabolic fuels such as glucose or fatty acids in the blood. Fluctuations of these fuels at receptive areas such as the hypothalamus  or liver  were considered to provide signals that influence food intake. For example, the group at Rockefeller headed by Jules Hirsch proposed that, when they are not at their maximum storage capacity, fat cells preferentially remove energy-rich fuels from the blood, creating short-term deficits that, in turn, trigger increased caloric intake. Variations in body fat among individuals were attributed to variations in the number of fat cells each individual carried, and fat cell number in turn was attributed to interactions of genetic and nutritional factors during developmental critical periods. More fat cells translated into a greater sink for ingested nutrients, creating a shortage of available energy for other tissues. The shortage could be compensated by consuming more food but at the expense of excess body fat .
An alternative possibility was that rather than the availability of metabolic fuels being the important factor, the actual amount of fat per se is sensed more directly, such that reductions in fat content triggered increased eating and surfeits in body fat triggered decreased eating. What was not known was the nature of a signal that could inform the brain as to the amount of fat stored in the various fat depots throughout the body. Results from the pioneering work of Doug Coleman and others using pairs of parabiotic rodents in which a small percentage of blood is shared between the two animals strongly suggested the existence of a circulating factor proportional to body fat that influences food intake . At about the same time, Dan Porte and I were exploring the relationship between the pancreatic hormone insulin and autonomic nervous system function using a dog model in Dan’s lab at the Seattle Veterans Administration Hospital. We were specifically interested in whether intravenously administered insulin could penetrate the blood-brain barrier and trigger neural reflexes to the pancreas. An unexpected finding was that insulin was present in small amounts in the cerebrospinal fluid (CSF) in control dogs and that CSF insulin increased shortly after we elevated insulin in the plasma . We pondered the question as to why insulin should enter the brain at all since nerve cells, unlike most other cells in the body, are insulin-independent; i.e., they do not require insulin to satisfy their glucose needs for cellular energy.
An important clue came from Porte’s work demonstrating that both basal insulin levels and glucose-stimulated insulin responses are directly proportional to body weight . Based on that, we reasoned that any cell expressing insulin receptors might respond to a change of insulin level as if there had been a change of adiposity. This, in turn, suggested the hypothesis that an experimentally-induced increase of brain insulin would be perceived as an increase of body fat when detected by brain cells expressing insulin receptors, and this would lead to decreased food intake. To test this hypothesis we continuously infused insulin at doses of 1, 10 or 100 mUkg-1d-1 for 10 d into the lateral cerebral ventricles of baboons , the study here honored as an Ingestive Classic. Insulin infusion led to significant, dose-related reductions in food intake and body weight in comparison to baseline periods during which artificial CSF was infused. Furthermore, infusion of pancreatic glucagon in the same molar dose as the largest insulin dose had no significant effect on food intake or body weight.
Over the next couple of decades, Dan Porte and myself and our colleagues developed optimal parameters for administering insulin into the brain and assessing its effects using rodent models, as well as the controls necessary to rule out illness or other alternative explanations for the altered food intake. We, as well as many other labs, systematically identified the distribution of brain insulin receptors and the mechanism by which insulin enters the brain from the blood. It should be noted that although several other groups found that administering insulin into the ventricles or directly into brain neuropil elicited hypophagia and loss of body fat, insulin action in the brain remained a somewhat controversial topic to many. In short, there were many skeptics and not a lot of interest (see review in ).
The situation changed greatly when leptin was discovered in 1994 . This breakthrough was also based on the earlier parabiosis work of Doug Coleman using ob/ob and db/db mice  suggesting that the lack of some circulating factor in ob/ob mice and the lack of a receptor for that factor in db/db mice led to their hyperphagia-obesity syndromes. The discovery of leptin had immediate important consequences. For one thing, as depicted in the figure, based upon the criteria we and others had established for identifying an adiposity signal to the brain, the decades of research that had been required to so-identify insulin were condensed into a very short period of time; i.e., it was already known how to proceed with the second purported adiposity signal, leptin. Another key consequence was the greatly accelerated movement of molecular biologists and molecular geneticists into the realm of ingestive behavior.
Today, several hormones whose secretion is proportional to body fat are known to influence receptors in the brain and to influence eating or energy metabolism. In addition to insulin and leptin, these include amylin , adiponectin  and perhaps others. These adiposity signals interact with other controllers of food intake in the regulation of body adiposity [14, 15].
In retrospect, we were quite lucky in identifying insulin as a potential adiposity signal to the brain. Pharmacological doses of insulin had to be administered, and while other labs replicated our basic findings, the ability of centrally-administered insulin to reduce food intake and body weight in rodents is small and often unreliable . The more recent demonstration that female mice lacking insulin receptors on neurons (NIRKO mice) become hyperphagic and obese , analogous to db/db mice that have non-functional leptin receptors being obese, lent important credence to the concept that signals proportional to body fat content can have a major influence on food intake and energy balance. That said, the importance of adiposity signals to food intake in freely-feeding individuals is not always clear. The observations that normal eating behavior can be dissociated from levels of plasma insulin and leptin , that insulin and leptin influence food intake by modifying the response to acute, meal-generated signals, and that non-homeostatic influences such as learning, social factors and stress have such a large influence , remind us that we still do not have a solid grasp of how all of the factors controlling food intake interact.
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