Meal Onset Research Articles

The central amygdala is involved in the conditioned but not in the meal-induced cephalic insulin response in the rat

The central nucleus of the amygdala (CEA) is considered to be involved in the regulation of autonomic correlates of fear. Its involvement in the control of autonomic functions other than elicited by fear has received little attention. The effects of a bilateral electrolytical lesion of the CEA on feeding related insulin responses have been analyzed in male Wistar rats. The cephalic phase of the insulin response is a vagally mediated elevation of plasma insulin concentration during the first minute after meal onset, before any increase in plasma glucose can be noticed. This response can also be entrained to environmental stimuli. The insulin response elicited under these conditions is due to conditioning. CEA lesioning abolished the conditioned insulin response but not the early insulin elevation during the presentation of food. The CEA lesion failed to affect plasma glucose levels in both the meal-induced and conditioned test situations. To our knowledge this is the first study that shows that the CEA is also involved in the organization of conditioned metabolic endocrine responses.

Metabolic rate and feeding behavior.

According to the ischymetric hypothesis, hunger is induced by the decrease of overall metabolic rate. In order to assess such a mechanism, it was necessary to monitor the muscular contraction-free metabolic rate designated "métabolisme de fond" (MF) in rats that were either resting or moving. MF was then examined in relation to either spontaneous or induced feeding patterns. A computerized open-circuit gas analysis system allowed us to monitor MF and behavior and to show that the onset of a spontaneous meal was preceded by a decrease of MF and its termination is preceded by a rebound of MF. Pharmacological blockade of utilization of both glucose and lipids enhanced feeding only to the extent that it reduced MF. These findings apply to pharmacotherapy because the anorexigenic effect of dexfenfluramine results from the enhancement of MF induced by the capacity of this drug to mobilize endogenous fat reserves and to so provide an endogenous meal that inhibits the exogenous meal. The ischymetric mechanism of hunger does not exclude important modulatory input from hormonal, circadian, and environmental factors in the control of feeding.

Monoaminergic activity at the level of the hypothalamus and striatum: relationship to anticipated feeding and pancreatic insulin responses

The present study examined monoaminergic activity at the level of the lateral hypothalamus (LH), ventromedial hypothalamus (VMH) and ventral striatum associated with the conditioned cephalic phase insulin release. Partially food-deprived male Wistar rats were divided into 3 groups. Two of the groups were conditioned to drink a 50% glucose solution each morning for 3 weeks; the control group recieved an amount of glucose equal to the amount drunk by the experimental animals with their afternoon meal. On test day, conditioned animals were sacrificed either just prior to glucose presentation or 2 min following consumption of the solution; control animals were sacrified at the same time. Gas chromatography/mass spectrometry was used to determine the levels of the monoamines noradrenaline (NA) dopamine (DA) and serotonin (5-HT), as well as their principal metabolites dihydroxyphenylethyleneglycol, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the LH and VMH. DA and DOPAC levels were assayed in the striatum. Although serum glucose levels were unchanged, animals conditioned and 5-HIAA at the level of the LH and VMH, increased NA content in the LH, increased DOPAC levels in the VMH as well as increases in the ratio of DOPAC to DA in the striatum. A regression analysis showed that 5-HIAA at the level of the LH related closely to serum insulin levels. We conclude that: (1) both pancreatic insulin responses and monoaminergic activity in discrete brain areas can be entrained to environmental stimuli predicting meal onset; and (2) since brain 5-HT activity was most closely associated with serum insulin rises, this monoamine neurotransmitter would appear to play a central role in the cephalic phase insulin response.

Feeding or exposure to food odors increases extracellular DOPAC levels (as measured by in vivo voltammetry) in the prefrontal cortex of food-deprived rats

The effects of feeding or of exposure to food odors (without opportunity to feed) on dopamine metabolism in the prefrontal cortex have been investigated in rats food deprived for 24 h. Dopamine metabolism was assessed by measuring extracellular DOPAC levels by in vivo voltammetry with carbon fiber electrodes. Feeding in fasted rats was accompanied by an increase in extracellular cortical DOPAC levels which gradually returned to basal levels within 90 min after the onset of meal. A similar, though slightly less pronounced, increase in cortical dopamine metabolism was found in fasted rats exposed to food odors but not allowed to feed. These results indicate that feeding or the olfactory stimulation associated with food presentation causes an increase in mesocortical dopaminergic neuron activity.

Liver phosphorylase activation during early phase of feeding behavior: A neurohumoral regulation

The mechanisms of liver glycogen depletion during the early phase of spontaneous feeding were examined in adult rats. A 40% increase in the activity of phosphorylase a, the active form of a key glycogenolytic enzyme, was detected 5 min after the onset of feeding, with a concomitant decrease of glycogen in the liver after 5 and 15 min. Within 60 min after the onset of feeding, the enzyme activity returned to the basal level and the glycogen content was restored. These metabolic responses were impaired by hepatic sympathetic denervation or by bilateral adrenodemedullation. It was concluded that the onset of meals may evoke an arousal of the sympatho-adrenal system including the hepatic innervation, and that activation of this system is important in stimulating liver phosphorylase activity and glycogenolysis during the early phase of spontaneous feeding.

Food deprivation dissociates pancreatic glucagon's effects on satiety and hepatic glucose production at dark onset

We compared the effects of different durations of pretest food deprivation on pancreatic glucagon's (PG) satiating and glycogenolytic actions in order to test the hypothesis that stimulation of hepatic glucose production causes PG's satiety effect. Rats were maintained on a 12:12 LD cycle (lights off: 1015) and deprived of food 45 min or 8, 12, 18, or 24 hr before intraperitoneal injection of 400 μg/kg PG. Testing began at 1015, the beginning of the dark phase. Food intake was not inhibited after 45 min of pretest food deprivation (30 min change, 2.5±4.0%, p<0.05), but was inhibited after 8 or more hr food deprivation. The largest inhibitory effect, 16.2±3.8%, p<0.01, occurred after 8 hr food deprivation. In separate experiments, rats were food deprived 45 min or 8 hr, similarly injected, and killed 10 min after refeeding for blood and liver samples. Hepatic glycogen content at meal onset was higher in rats deprived 45 min than in rats deprived 8 hr ( 3.2±0.3 vs. 1.7±0.3% liver weight, p<0.01), and PG injection produced a higher level of hepatic vein blood glucose in the less deprived rats ( 196±5 vs. 168±12 mg/dl, p<0.05). Thus, in rats tested at the beginning of the dark phase of the LD cycle after 45 min or 8 hr food deprivation, there is an inverse relation between PG's potencies to inhibit food intake and to stimulate hepatic glucose production. We conclude that PG's glycogenolytic effect does not account for its effects on meals in 0–8 hr food deprived rats tested at the beginning of the dark phase of the circadian cycle.

Guanosine diphosphate binding to brown adipose tissue mitochondria is increased after single meal.

A single meal results in an increased thermic activity of brown adipose tissue (BAT). The purpose of the present studies was threefold: 1) to identify major metabolic origins involved in this thermic response, 2) to determine the effect of meal composition on it, and 3) to determine time changes in postprandial brown fat thermogenesis. Wistar rats were trained to eat during 2 feeding sessions/day. On the days of the experiment, rats received a test meal for 2 h, and respective control rats were simultaneously meal deprived. The animals were killed at one or more time points after meal onset, and their BAT was removed for determination of mitochondrial guanosine diphosphate (GDP) binding to indicate rate of uncoupled respiration (expts 1 and 3) or Na+-K+-ATPase activity representing coupled respiration (expt 2). Meal taking was followed by an 85% increase in GDP binding (P less than 0.001). In contrast, Na+-K+-ATPase activity was not altered by a test meal of a similar composition. The largest meal-induced rise in mitochondrial GDP binding was evident during the early postprandial hours, and it was greatly reduced by 10 h after meal onset. Expressed per total interscapular brown fat depot, a high-carbohydrate meal caused a greater increase in GDP binding than an equicaloric high-fat meal. Our data indicate that the BAT proton conductance pathway is activated by a single meal.

Cephalic phase of insulin secretion and food stimulation in humans: a new perspective.

Insulinemia and glycemia were measured at a 1-min interval at the hour of a lunch meal in human subjects. When no food was presented to naive subjects (n = 4), cyclic oscillations of insulinemia were found (period, 12-20 min; amplitude, 2.8-10.3 microU/ml). It is proposed that these spontaneous oscillations must be taken into consideration when evaluating the insulin response on cephalic contact with food stimuli; they might otherwise constitute a source of artifacts. Four subjects were then submitted to a series of four test meals scheduled at a 1-wk interval. Although their prandial glycemia remained comparable with preprandial values for the first 16 min of the meals, insulinemia often exhibited early peaks (within a few min after meal onset) whose amplitude appeared related to palatability conditions. Evidence suggests that the insulin peaks triggered by cephalic stimulation are Pavlovian reflexes that become conditioned to the test situation. A typical neuroendocrine response to alimentary frustration is also described. The results are discussed in perspective with animal works, in terms of the effects of neuroendocrine events on feeding behavior.

Meal-induced brown fat thermogenesis and thyroid hormone metabolism in rats.

The relationship between the meal-induced increase in brown adipose tissue (BAT) thermogenesis, determined by the level of GDP binding to BAT mitochondria, and thyroid hormone metabolism have been examined. A single low-protein, high-carbohydrate meal resulted in a significant increase in the thermogenic activity of BAT. This effect on BAT thermogenesis was accompanied by significant increases in activity of thyroxine 5'-monodeiodinase in the BAT (P less than 0.05) and liver (P less than 0.02) but not with any significant changes in serum concentrations of the thyroid hormones. The stimulatory effects of the meal on BAT thermogenesis and hepatic thyroxine (T4) to triiodothyronine (T3) conversion persisted at least as late as 24 h after meal onset. Food deprivation for 40 h was associated with large reductions in serum concentrations of T3 (P less than 0.01) and T4 (P less than 0.001), but deprivation for 18 h had no significant effect on serum T3 and T4 concentrations. Our data indicate that the meal-induced increase in BAT thermogenesis can be independent from changes in serum concentrations of thyroid hormones and suggest that T3 produced in BAT in response to feeding may play a role in the thermic response of this tissue to meals.

Spontaneous and 2DG Induced metabolic changes and feeding: The ischymetric hypothesis

A computer-controlled calorimeter which simultaneously measured respiratory exchanges, locomotor activity, and meal patterns, was used to study Total Metabolic Rate (TM), Locomotor Free Metabolic Rate (LFM), and Respiratory Quotient (RQ) in relation to spontaneous and 2DG induced Food Intake in freely-feeding rats. It appeared that spontaneous and 2DG induced feeding was preceded by a consistant drop of LFM starting about five minutes before a meal and reaching its nadir at the onset of a meal. The simultaneous determination of the RQ did not show any systematic change that would have reflected either a lipo- or a gluco-privic origin of the LFM drop and meal onset. Therefore, the results are in agreement with the ischymetric hypothesis of the control of food intake which proposes that the final signal triggering hunger and satiety is the intensity of cell power production (measured in this experiment through the LFM parameter) which is independent of the glucidic lipidic or protidic origin of the substrate(s) supplying power production.

On-line continuous measurement of blood glucose and meal pattern in free-feeding rats: The role of glucose in meal initiation

LouisSylvestre 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 causally related to meal onset. These studies suggest that the premeal decline in blood glucose is among the signals for meal initiation.

Metabolic responses to a meal during rest and low-intensity exercise

The effects of intermittent exercise on increases in metabolic rate and plasma insulin, glucose, and triglyceride concentrations at 1, 2, and 3 h after an 800-kcal meal were examined in six healthy volunteers. Mean plasma insulin concentrations were significantly lower (−61%) at the end of a 15-min exercise session on a stationary bicycle (50 W) at 1 h after the meal, compared to insulin concentrations when subjects rested throughout the test, but had returned to normal resting levels by 30 min after the end of the exercise bout. Mean plasma glucose concentrations were not significantly different at the end of the exercise bouts than they were at comparable times of the resting study, but were about 20 mg/dl higher 30 min after the exercise bouts. Plasma triglyceride concentrations increased by approximately 50% after the meal, and this effect was not influenced by exercise. Resting metabolic rate increased by 19.9 ± 2.1, 20.6 ± 2.1, and 15.1 ± 2.4 kcal/h at 1, 2, and 3 h after meal onset, and the metabolic rate during exercise increased by 13.8 ± 4.4, 16.8 ± 3.5, and 11.6 db 3.4 kcal/h at 1,2, and 3 h after meal onset. These data suggest that postprandial exercise would be no more beneficial than preprandial exercise in increasing energy expenditure.

Metabolic and feeding patterns: role of sympathetic and parasympathetic efferent pathways

The continuous transfer of fuel from the blood to tissues, and its adjustment to the rate of energy metabolism involve close relationships between the control of endogenous stores and that of the periodic intake of food. Neural and blood-borne signals to the brain and efferent sympathetic and parasympathetic pathways seem responsible for three different metabolic and feeding cycles. The matching of input and output of glucose to and from the blood, i.e. the regulation of the blood glucose level proper, is achieved by a short-term feedback mechanism which involves the action of insulin and glucagon on hepatic glucose production and peripheral glucose utilization. Oscillations in level of blood glucose, plasma insulin and glucagon in 8–11 min cycles, as observed in certain species, presumably reflect the play of this short-term regulation of the blood glucose level. The respective role of a pancreatic feedback and of a neural loop in this short-term regulation is discussed. Signals to brain targets and efferent pathways determine the periodic onset of meals after the energy ingested in the preceding meal has been exhausted in free-fed and briefly deprived rats. New evidence has been provided that the fall in blood glucose level exerts a decisive and direct action on the brain to determine meal onset and/or meal size. Superimposed on this prandial periodicity, a lipostatic mechanism modulates the feeding pattern in a dark-light periodicity by the alternation of fat synthesis and fat mobilization. The effects of VMH lesions and vagotomy, either combined or separately, on daily metabolic and feeding patterns suggest that the neural input to the pancreas and adipose tissues plays a primary role in this endogenous cycle and is also involved in the regulation of a constant fat body mass.

Meal to meal energy balance in rats

Meal to meal energy balance was examined in thirty-eight simultaneous recordings of feeding pattern and O 2 consumption in six rats. The mean difference between energy intake in a meal and energy expenditure until the onset of the next meal was found positive at night and negative during day time. At night the excess of meal intake over meal to meal expenditures was decreasing from the beginning to the end of the night and was strongly correlated to meal sizes. During day time meal to meal deficit was decreasing from the beginning to the end of the period but was not correlated to meal sizes. These meal location and size effects on the meal to meal energy balance were not determined by an effect of these factors on metabolic rate. No indication was provided that meal to meal energy balance was influenced by a “meal induced thermogenesis.” Rather an evolution from the beginning to the end of the night of the correlation between meal size and durations of meal to meal intervals was found to be parallel to the evolution of positive meal to meal energy balance throughout the night. From these data it is concluded that at night a dual utilization of meal caloric intake (current energy metabolism plus fat storage) and a dual source of fuel during the day (food plus mobilized fats) determine time and mechanism of meal onset.

Reflex insulin response associated to food intake in human subjects

The occurrence of a reflex insulin discharge at the beginning of a meal, and its possible influence on intake were studied in 7 normal weight humans. Each subject was tested twice under three standard meal conditions. The evolutions of insulinemia and glycemia were recorded over an 84 min observation period, starting 2 min before food presentation. Blood was drawn continuously from an antecubital vein, and collected in 1-min samples for the first 30 min, and then in 3-min samples. The average glycemia curve was stable until some 18–20 min after meal onset. By contrast, a significant rise in plasma insulin appeared as early as the 4th min after meal onset and it is hypothesized to be preabsorptive, of cephalic and/or gastric origin. However, inter-test variations were large even in the same person. Schematically, three types of early insulin responses were observed: high and/or sustained rise, moderate and/or short increase, moderate decrease in plasma insulin. The shape of the early insulin response was not related to any meal characteristic. The potential biological and behavioral significance of the early insulin release is discussed.

Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon.

Intraperitoneal injections of antibodies to pancreatic glucagon at the onset of the first meal after 12 hours of food deprivation increased meal size 63 percent and meal duration 74 percent in rats. The antibodies also reduced the increase in hepatic vein blood glucose that occurred during meals in control rats, but did not affect the prandial increase in portal vein blood glucose. These results suggest that, under these conditions, pancreatic glucagon is necessary for the normal termination of meals.

Liver glycogen content decreases during meals in rats

The effects of feeding on liver glycogen content and blood glucose in the hepatic and hepatic portal veins were investigated in rats. Liver glycogen content decreased about 25% during meals both in rats refed after 12 h food deprivation (23 +/- 1 to 17 +/- 1 mg glycogen/g liver) and in ad libitum-fed rats taking fully spontaneous meals (44 +/- 2 to 32 +/- 2 mg/g). Liver glycogen began to increase within 30 min after meals in ad libitum-fed rats. Hepatic vein blood glucose levels at meal onset (118 +/- 4 mg/dl in the food-deprived rats, 127 +/- 4 in ad libitum-fed rats) and at meal end (155 +/- 3 and 166 +/- 5 mg/dl, respectively) were similar in the two groups. Portal vein blood glucose increased during meals in the previously food-deprived rats (83 +/- 4 to 116 +/- 6 mg/dl) but not in the ad libitum-fed rats (127 +/- 5 to 132 +/- 3 mg/dl). Mechanisms that may elicit prandial glycogenolysis and the possible role of this effect in the production of meal ending satiety are discussed.

Glucose control in mobile type 1 (insulin-dependent) diabetic patients by means of a semi-automatic feedback controlled insulin infusion system.

A portable insulin dosing device (Siemens) was used together with a programmable pocket calculator and a glucose analyzer for short-term adaptation of continuous intravenous insulin infusion to blood glucose alterations. A special algorithm was developed which utilizes a given blood glucose value and the glucose rate of change obtained from two to four consecutive samples as input variables. In contrast to current techniques of feedback-regulation, which require continuous glucose monitoring, intermittent blood sampling allows greater mobility of patients. With the semi-automatic feedback system, euglycaemic control was obtained for 12-h periods in ten Type 1 (insulin-dependent) diabetic patients (maximum value 9.50 mmol/l, minimum value 2.83 mmol/l). Severe hypoglycaemia occurred in no case and additional control by glucose infusion appeared to be unnecessary. Light exercise after termination of insulin dose for standard meals led to glycaemic excursions with a rapid decrease (mean 1.08 +/- 0.09 mmol/l), followed by a rebound (0.59 +/- 0.07 mmol/l) in each patient. The amplitude of these excursions decreased with increasing distance from the peak of the meal dose. Comparison of feedback-control alone with feedback by glucose plus preprogrammed dose (4 U/h) at the onset of the test meal revealed lower post-prandial glucose levels (post-prandial maximum +/- SEM: 6.49 +/- 0.18 versus 7.71 +/- 0.79 mmol/l) and a lower infusion rate of insulin for the combined regimen (mean post-prandial maximum +/- SEM: 8.4 +/- 1.2 versus 12.0 +/- 0 IU/h). The system is useful for programming of portable infusion devices and studies based on euglycaemic control in unrestrained patients.

Theophylline disrupts diurnal rhythms of humoral factors with loss of meal cyclicity

To test the possibility that theophylline induced circadian disappearance of food intake might depend upon rhythmic disruption of blood glucose, insulin and free fatty acids (FFA), theophylline was administered chronically. This markedly lengthened postprandial intermeal intervals during the dark, and induced approximately identical intermeal intervals and identical meal sizes in the light and dark periods. In contrast to the clear light-dark dependent oscillations of serum glucose, insulin and FFA in the controls, the theophyllinized rats lost circadian fluctuation of each of these three chemical substances. Further, theophyllinized rats, unlike controls, had no time-dependent fluctuation in the levels of these substances at − 120, −60 or −15 min preceding the onset of the first meal before the dark. These findings, together with previous reports, explain the disappearance of nocturnal feeding rhythm in theophyllinized rats in terms of functional destruction of circadian regulation in the hypothalamus which modulate the production of chemical determinants of food intake.

Pancreatic glucagon and postprandial satiety in the rat

The hypothesis that administration of pancreatic glucagon inhibits feeding by eliciting satiety for food was tested against several behavioral and physiological criteria of specificity. The effects of intraperitoneal glucagon injections on intake of a palatable milk diet were tested in rats maintained with ad lib access to pelleted diet. Injections of 25–800 μg/kg glucagon administered at meal onset inhibited meal size by 17–36%, but did not affect the normal postprandial behavioral satiety sequence or elicit any behavioral signs of toxicity. Latency to rest and intermeal interval were not affected. Glucagon decreased meal size by specifically inhibiting feeding during the terminal phase of the meal without affecting feeding earlier in the meal. This was also the case when glucagon was injected 4 min prior to meal onset. This range of glucagon doses did not affect water intake in water deprived rats consuming fluid volumes comparable to the milk intakes. They also did not affect body temperature. Finally, injection of 400 μg/kg glucagon after the initial exposure to a novel drinking fluid was not sufficient to form a conditioned taste aversion in a two bottle preference test. These data, together with reports that circulating pancreatic glucagon levels increase during meals, strongly suggest that pancreatic glucagon is involved in the production of postprandial satiety.