The Insulin Story: A 25-Year Perspective

The hypothesis that physiological signals provide the CNS with information about energy stores to influence ingestive behavior is an attractive one, and it has generated much research into whether insulin is such an agent (Woods, 1995). Although insulin had been known to be active in the periphery, it was a surprise to many when insulin was found to be present in the central nervous system. Previously, it had been established that the weight of animals changed slowly in response to experimental manipulation and returned to its previous level when the manipulation was removed. Therefore, it was proposed that body weight was regulated. The preferred mode of this regulation would be behavioral, mainly by adjusting food intake, although other strategies with greater costs, such as alterations in metabolism, would also be available. For behavior to be aVected, a regulatory signal from the gut to the CNS would (1) have to exist in amounts proportional to body fat and circulate in the blood, (2) acquire access to the CNS and be able to interact with the brain, and (3) have to have predictable eVects on behavior and metabolism. Insulin meets these criteria. Basal circulating insulin increases or decreases with higher or lower levels of body fat. In addition, in response to a glucose infusion or food ingestion, the peaks of insulin associated with these manipulations are higher in the animals with higher adiposity (and basal insulin is higher). The enhanced level of insulin in obese rats is accompanied by peaks of blood glucose that are indistinguishable in magnitude from those measured in lean animals. Insulin levels correlated significantly with adiposity under both basal and absorptive conditions. Evidence that insulin has eVects on food intake and body weight when present in the brain came from a study using baboons (Woods, Lotter, McKay & Porte, 1979). Infusions of insulin at doses up to 100 lUnits/kg/day (over several days) produced incrementally larger decreases in food intake. Food intake reduction by peripheral insulin administration was demonstrated in both baboons and rats and was enhanced when glucose was infused at the same time (Woods, Stein, McKay & Porte, 1984). Experiments in dogs revealed that i.v. administration of insulin resulted in an increase not only in the periphery but also, with a longer latency to plateau, in the cerebrospinal fluid. This finding opened the possibility that insulin gets into the brain. Initially it was assumed that insulin entered the CNS by passing into the cerebrospinal fluid (CSF) from the bloodstream via the choroid plexus from which it could then diVuse into the interstitial fluid of the brain. Experiments in rats showed that CSF insulin levels increased almost instantly when insulin was infused peripherally (SteVens, Scheurink, Porte & Woods, 1988). However, computer models based on these data suggested that the insulin movement was from the blood to the interstitial fluid and was receptor mediated. Insulin receptors were found on the lumenal side of brain capillaries and were determined to regulate the amount of insulin that enters the CNS via active transport. The rate of transport is related to the metabolic state of the animal.