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A new framework for understanding the control of feeding behavior, with special emphasis on the evolution of hunger, the initiation of feeding, and its dependence on patterns of blood glucose, is the subject of this review. A perspective on the current status and future directions of this search for a more complete understanding of the regulation of feeding behavior in laboratory rats and humans is presented including theoretical and experimental components. First, a historical perspective on the role of blood glucose in the control of feeding is presented. Next, the theoretical approaches that have been applied to the control of feeding and had a strong influence on experimental feeding research are summarized. This is followed by a statement and overview of a current theory that has emerged from studies of the role of transient declines in blood glucose in the control of meal initiation. The current working hypothesis that transient declines in blood glucose are endogenous metabolic patterns that are detected and recognized by the central nervous system and are mapped into meal initiation in rats and are correlated with meal requests in humans are then presented. Then, the experimental studies on meal initiation and its dependence on patterns of blood glucose, first in rats and then in humans, are reviewed in detail. Finally, the future directions of the work, limitations, and the implications for the understanding of the control of feeding behavior and the regulation of energy balance are discussed.

The mechanisms by which OB protein controls food intake and energy balance are unknown. Therefore, we investigated the effects of a novel modified human recombinant OB protein (Mod-OB) on spontaneous feeding patterns, body weight, running wheel activity, and ovarian cycling in female rats. Mod-OB or vehicle was injected (4 mg . kg-1 . day-1 sc) for 2 ovarian cycles (8 days) using a within-subjects design. Observations were continued for five ovarian cycles after injections; treatments were then reversed. Mod-OB reduced food intake approximately 20% from injection day 1 to postinjection day 2. Body weight was reduced from injection day 3 to postinjection day 15 (maximum decrease, 25 +/- 4 g, postinjection days 3 and 4). Food intake was reduced due to decreases in nocturnal meal size, which appeared to be superimposed on the normal pattern of spontaneous feeding (i.e., reductions in meal size at estrus). Mod-OB did not significantly affect diurnal food intake or meal patterns, failed to alter wheel running, and did not disrupt the rats' ovarian cycles. We conclude that chronically administered Mod-OB reduces food intake in female rats by selectively affecting the mechanisms controlling meal size.

The aim of these studies was to determine if meal requests and changes in hunger ratings in humans were related to spontaneous changes in blood glucose concentration. In our first study, 18 healthy subjects were acutely isolated from food ant time cues. Blood glucose was continuously monitored online and visual analog ratings of hunger were obtained following an overnight fast. Spoken meal requests, if they occurred, were also recorded. In 83% of the subjects, both the perception and behavioral expression of hunger, as assessed by changes in hunger ratings and meal requests, were preceded by, and correlated with, brief, transient declines in blood glucose (nadir: -10% at 27 min). The pattern, magnitude and time course of these declines was similar to those observed in rats. This significant association, between increased expression of hunger and declines in blood glucose, is being tested in a second, ongoing study using acute insulin infusions to mimic spontaneous transient declines in blood glucose. Each subject was studied twice: either insulin or saline was infused while hunger ratings were obtained. Preliminary results in five subjects indicate that hunger ratings increased after insulin-induced transient declines in blood glucose. No change in hunger ratings occurred when blood glucose concentration was stable. These results suggest that this temporal pattern of blood glucose reflects an antecedent physiological event or provides a signal related to the expression of hunger in humans. Further understanding of human eating may result from investigation of the complex interaction of physiological and other factors in an experimental setting that allows the expression the behavior under study.

Louis-Sylvestre and LeMagnen have suggested that the premeal decline in blood glucose is or reflects a signal for meal initiation in rats. In order to extend and test this hypothesis, a computer controlled system for continuously and concurrently measuring blood glucose and food intake in free-feeding rats was developed. In 18 experiments (with and without intravenous saline infusions), blood glucose declined about 12 minutes prior to meal onset. During 2-1/2 hours of observation, no decline in blood glucose and no meal occurred in 19 other experiments. In 7 experiments in which 10 percent glucose was infused IV to partially block the premeal decline (average blockade = 46.5%), the subsequent meal was significantly delayed. These results suggest that the pre-meal decline in blood glucose is not only correlated with but is also caudally related to meal onset. These studies suggest that the premeal decline in blood glucose is among the signals for meal initiation.

We have examined some of the factors involved in the control of food intake and integrated the data using methods of systems analysis from biomedical engineering. The central hypothesis is that energy stored in the body is a regulated variable. Alterations in the quantity of stored calories initiates changes designed to restore the store of calories to its original level. These responses are both short-term and long-term in nature. They involve integrating data on the quantities of protein, carbohydrate, and lipid stores in the body, probably through such feedback signals as amino acids, glucose, glycerol, and free fatty acids.

To assess the strength and time course of the functional coupling between transient declines in blood glucose and meal initiation, access to food was prevented throughout declines followed by restoration of access to food when glucose returned to baseline. Neither preventing access to nor the absence of food affected the time course of the decline in blood glucose and the latency to food seeking behavior. When access to food was restored six to eight minutes after the blood glucose returned to baseline, no food seeking behavior or feeding occurred until after a second decline in glucose had occurred about one hour later. However, when access to food was restored before glucose returned toward baseline, feeding began within two minutes. Blood glucose did not decrease following presentation of novel foods and feeding occurred rapidly without a prior decline in blood glucose. Therefore, transient declines in blood glucose strongly signalled food seeking and meal initiation but this functional coupling was of short duration (approximately 12 min) and persisted less than six minutes after the blood glucose had returned to baseline. The transient decline in blood glucose appears to be an endogenous, glucose dependent cue for food seeking and meal initiation.