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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.

Regulatory functions of glycogen stores and blood glucose on human appetite, particularly relating to exercise, are not fully understood. Ten men (age 20-31 yr) performed glycogen-depleting exercise in an evening, ate a low-carbohydrate dinner, and stayed overnight in the laboratory. The next day, blood glucose was monitored continuously for 517 +/- 23 (SE) min. Subjects had access to high-fat and high-carbohydrate foods after baseline glucose and respiratory quotient were determined. In the afternoon, 1 h of moderate exercise was performed. Baseline respiratory quotient was 0. 748 +/- 0.008, plasma free fatty acids were 677 +/- 123 micromol/l, insulin was 4.8 +/- 0.5 microU/ml, and leptin was 1.9 +/- 0.3 ng/ml. Postabsorptively, 8 of 10 meals were initiated during stability in blood glucose. Postprandially, the association between meal initiation and blood glucose declines became significant (chi(2) = 7. 82). During moderate exercise, blood glucose initially decreased but recovered before completion. When the glycogen buffer is depleted, meal initiation can occur during blood glucose stability; the relationship between blood glucose declines and meal initiation reestablishes with refeeding.

We assessed the extent to which a possible synchronization between transient blood glucose declines and spontaneous meal initiation would lend support to the interpretation of a preload study with isoenergetic (1 MJ) isovolumetric high-fat or simple carbohydrate (CHO) preload drinks. Ten men (18-30 yr) fasted overnight and then were time blinded and made aware that they could request meals anytime. At first meal requests, volunteers consumed a preload; ad libitum meals were offered at subsequent requests. Postabsorptively, transient declines in blood glucose were associated with meal requests (chi(2) = 8.29). Subsequent meal requests occurred during "dynamic declines" in blood glucose after the peak induced by drink consumption (100%). These meal requests took twice as long to occur after high-fat than after CHO preloads (fat = 126 +/- 21, CHO = 65 +/- 15 min), consistent with differences in interpolated 65-min satiety scores (fat = 38 +/- 8.2, CHO = 16 +/- 4). Postprandially, transient blood glucose declines were associated with meal requests (chi(2) = 4.30). Spontaneous meal initiations were synchronized with transient and dynamic blood glucose declines. Synchronization of intermeal interval and dynamic declines related to higher satiating efficiency from high-fat preloads than from simple CHO preloads.

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action.

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 potent hypophagic effect of OB protein (OB) is well established, but the mechanism of this effect is largely unknown. We investigated the effects of chronic administration of a novel modified recombinant human OB (Mod-OB) with a prolonged half-life (>48 h) on ad libitum food intake, spontaneous meal patterns, and body weight in 24 adult, male Sprague-Dawley rats (body weight at study onset: 292 g). Single daily subcutaneous injections of Mod-OB (4 mg/kg daily) for 8 consecutive days significantly reduced ad libitum food intake compared with vehicle injections from injection day 3 through postinjection day 3. Mod-OB-injected rats ate between 4.5 and 7.1 g (or 13-20%) per day less than controls, with the reduction primarily occurring during the dark period. Body weight gain was significantly decreased in response to Mod-OB from injection day 8 until postinjection day 4, with a maximum difference of 24 g on postinjection day 3. The reduction of food intake by Mod-OB was mainly due to a 21-34% decrease in nocturnal spontaneous meal size. There was no significant effect of Mod-OB on nocturnal meal frequency or duration. Mod-OB also did not reliably affect the size, duration, or frequency of diurnal meals. Mod-OB-injected rats displayed no compensatory hyperphagia after the injection period. These results indicate that chronically administered OB selectively affects the mechanisms controlling meal size in male rats.

Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.

Recently, glucagon-like peptide-1-(7-36) amide (GLP-1) and leptin have been implicated in the regulation of food intake. In the present study, we compared the effects of third ventricular administration (i3vt) of leptin (3.5 micrograms) and GLP-1 (10.0 micrograms) on short-term food intake and c-Fos-like immunoreactivity (c-FLI) in hypothalamic, limbic, and hindbrain areas in the rat. Relative to controls, infusion of leptin or GLP-1 (3 h before lights off) significantly reduced food intake over the first 2 h in the dark phase (53 and 63%, respectively). In different rats, infusion of leptin or GLP-1 elevated c-FLI in the paraventricular hypothalamus and central amygdala. Furthermore, leptin selectively elevated c-FLI in the dorsomedial hypothalamus, whereas GLP-1 selectively elevated c-FLI in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, and arcuate hypothalamic nucleus. The fact that most of the c-FLI after leptin or GLP-1 administration was observed in separate regions within the central nervous system (CNS) suggests different roles for leptin and GLP-1 in the CNS regulation of food intake and body weight.

Previous studies have shown that a brief rise in plasma insulin followed by a transient fall and rise in blood glucose precede the initiation of feeding in nondeprived rats. In this study, a cholinergic agonist, bethanechol chloride, which is known to induce a brief spike in plasma insulin, was infused intravenously in an attempt to induce transient declines in blood glucose and meal initiation in free-feeding rats. When the blood glucose response to bethanechol chloride administration met the criteria for a transient decline in blood glucose, meal initiation occurred within 20 min in nine out of ten trials. However, if the blood glucose response to bethanechol chloride administration failed to meet the criteria for a transient decline in blood glucose, meal initiation did not occur. The frequency of successful induction of feeding was higher in the late light cycle (80%) compared with the early light cycle (14%) of the photoperiod. These results suggest that cholinergic stimulation can induce feeding only after a brief fall and rise in blood glucose. The blood glucose and behavioral responses to the cholinergic stimulus appear to be strongly dependent on the metabolic state of the animal. These results further strengthen the evidence for a causal relationship between transient declines in blood glucose and meal initiation in free-feeding rats.

Recent studies suggest that alterations in autonomic neural activity may mediate the obese state observed following ventromedial hypothalamic (VMH) lesion. To assess the role of these alterations in the increased glucose responsiveness of the beta-cell observed in this state, we have determined the sensitivity of insulin secretion to norepinephrine or/and acetylcholine in statically incubated pancreatic islets from rats 30-40 days after VMH lesion. In islets from VMH-lesioned rats compared with islets from sham-operated and intact rats, the acetylcholine dose-response curve was shifted down and to the right, indicating a decreased sensitivity, whereas the norepinephrine dose-response curve was translated to the left, indicating an increased sensitivity. The interaction profile, which summarizes combined neurotransmitter exposure on insulin secretion, was shifted in the direction of net inhibition. Thus it was concluded that, following VMH lesion, autonomic neurotransmitter sensitivity of the pancreatic beta-cell was altered. It is suggested that these alterations play a role in the adaptation of the beta-cell to the experimentally induced obese state.

We have quantitatively characterized the interaction of several concentrations of norepinephrine and acetylcholine applied simultaneously on insulin secretion in response to an intermediate glucose concentration (10 mM) from statically incubated pancreatic islets isolated from normal rats. When either norepinephrine or acetylcholine were applied alone, insulin secretion was respectively inhibited or enhanced in a dose-dependent manner. When combinations of norepinephrine and acetylcholine were applied simultaneously to the islet, insulin secretion was enhanced, inhibited, or not affected. The net effects of the interaction of norepinephrine and acetylcholine on insulin secretion were not only a function of the concentration of each neurotransmitter but also the relative concentrations of both neurotransmitters. Analysis of these interaction data suggests that 1) insulin secretion is the result of a complex interaction between sympathetic and parasympathetic neural and metabolic inputs; 2) norepinephrine and acetylcholine modulate insulin secretion primarily by direct action on the beta-cell membrane; 3) insulin secretion is more sensitive to perturbations in norepinephrine concentration than acetylcholine concentrations under these experimental conditions; and 4) the autonomic nervous system has the potential to play a major role in the control of insulin secretion in response to glucose.

The heterogeneous nature of the experimental obesities induced by ventromedial hypothalamic (VMH) lesion and high fat diet (HFD) have been demonstrated by comparing VMH-lesioned and sham-operated rats fed a HFD or low fat diet (LFD). VMH rats had increased fat mass serum insulin and serum triglycerides but lower serum glucagon and smaller salivary glands than sham-operated animals. The body weight of HFD obese rats was intermediate between VMH and sham-operated animals on the LDF. Liver and fat pad weights showed effects of lesions and diet. Diet did not affect plasma glucagon or insulin. Pair-feeding VMH rats with sham-operated rats prevented weight gain but did not prevent the increase in insulin and fall in glucagon. Studies of insulin secretion from isolated perifused islets showed that basal and both phases of stimulated secretion were significantly increased in VMH groups. The changes in plasma insulin, plasma glucagon, and salivary gland weight in VMH groups are interpreted as showing decreased activity of the sympathetic nervous system following VMH lesions.

It has been suggested that increased insulin secretion after ventromedial hypothalamic (VMH) obesity is mediated by decreased sympathetic and increased parasympathetic neural input. The evolution of pancreatic islet adaptation was studied from 1 to 130 days after VMH lesion in rats by assessing the sensitivity of insulin secretion from incubated isolated islets to 10 mM glucose and selected acetylcholine and norepinephrine concentrations. Insulin secretion in response to glucose increased by 1 day, reaching a twofold plateau from 7 to 130 days. Sensitivity to norepinephrine increased by 1 day, whereas sensitivity to acetylcholine decreased by 2 days, and both remained altered up to 130 days. These data suggest that elevated plasma insulin concentrations characteristic of VMH obesity were associated with increased insulin secretion in response to glucose before decreased sensitivity to acetylcholine and concurrent with increased sensitivity to norepinephrine. We conclude that these compensatory responses, which shift the islet to a new operating point secondary to altered neural input, are essential to pancreatic adaptation in VMH obesity.

The objective of these studies was to determine the impact of enhanced insulin response to glucose (glucose responsiveness) and altered neurotransmitter sensitivity of the pancreatic islet previously observed after ventromedial hypothalamic (VMH) lesion on the glucose regulatory system in the whole animal. Female Wistar (220 g) rats received bilateral electrolytic VMH lesions and were implanted with cardiac and femoral cannulas under anesthesia. After recovery, experimental studies were conducted in 2-h-fasted lightly heparinized conscious rats. Plasma glucose declined at 1 and 2 wk after lesion and returned gradually to basal levels by 4 wk, whereas plasma insulin was elevated at 1 wk and remained elevated at 4.5 wk after lesion. Glucose responsiveness was increased threefold 1 wk after lesion. Acetylcholine sensitivity, measured by insulin response to an acetylcholine analogue, was decreased at 1, 2, and 4 wk after lesion, whereas norepinephrine sensitivity, measured by norepinephrine inhibition of the insulin response to intravenous glucose, was significantly increased 1 wk after VMH lesion. These studies suggest that the observed alterations at the level of the pancreatic islet led to a shift in the operating point of the glucose regulatory system of the whole animal and that changes in neurotransmitter sensitivity reflect a pancreatic adaptation subsequent to the establishment of enhanced glucose responsiveness. This shift in operating point may be secondary to altered neural input and may be essential to pancreatic and, thus, metabolic adaptation to the VMH lesion-induced obese state.

The chronic effects of removal of parasympathetic neural input to the pancreas on in vitro insulin secretion were assessed. Groups of Wistar and Long-Evans rats received total subdiaphragmatic vagotomy or sham operation. Four to ten weeks later, after the return of food intake and body weight in the vagotomized groups to values similar to the sham-operated groups, pancreatic islets were isolated and statically incubated with selected concentrations of glucose and acetylcholine. Two experimental protocols were used. In the first experiment, insulin secretion in response to basal (5 mM) glucose was 59 +/- 15 (SE) and 65 +/- 13% greater in islets from the vagotomized Wistar and Long-Evans groups, respectively, than in the corresponding sham groups. The enhancement of insulin secretion by several doses of acetylcholine observed in islets from sham-operated groups was totally absent in islets from both vagotomized strains. In the second experiment, insulin secretion was determined in response to selected glucose concentrations by using islets from Wistar rats. An upward and leftward shift of the dose-response curve was observed in the vagotomized group causing 5 mM to become a stimulatory glucose concentration and increasing the stimulatory potency of 10 mM glucose. These results suggest that interruption of vagal input to pancreatic beta-cells may induce a compensatory increase in responsiveness to glucose and a functional suppression of acetylcholine receptors. These data provide further support for the hypothesis that vagal input plays a functionally important role in the control of insulin secretion and maintenance of acetylcholine sensitivity.