Hepatic Glucoreceptors Research Articles

Regulatory Impact of Intra-Hepatic Carbohydrate and Lipid Metabolism

The first evidence that the liver can afferently contribute to regulatory activities comes from studies on regulation of food intake. The hepatic afferent pathway has been shown to be responsive to glucoprivic as well as lipoprivic stimuli. Similarly to regulation of food intake, it has been reported that the liver may afferently contribute to the metabolic regulation of exercise. The best reported evidence of this view is the observation that the decrease in insulin and the increase in glucagon and noradrenaline levels during exercise are diminished in hepatic vagotomized rats (Lavoie et al., 1989). The concept behind these observations is that the liver, through the existence of hepatic glucoreceptors, is responsive to a decrease in glycogen content or to some metabolites of the glycolytic chain related to liver glycogen content. There is also some evidence that lipids in the liver may have some regulatory impact inside and outside the liver. Recent interest in looking at lipid metabolism in liver has been spurred by the observation that the increased flux of lipids through the hepatic portal vein has been associated with increased risks of metabolic and cardiovascular abnormalities. To explore this avenue, a 10% triglyceride emulsion was infused into either the portal or a peripheral vein of rats for 48 hrs while another group of rats was acutely infused for 2 hrs into the portal vein. The results indicate that all of these lipid infusions resulted in an increase in liver lipid infiltration, which may be associated with the development of a state of hepatic and peripheral insulin resistance.

Sensing hypoglycemia: the ventromedial hypothalamus.

Hypoglycemia as a limiting factor in the treatment of diabetes mellitus with insulin was apparent even before the hormone was administered to patients. A passage in a biography of Banting notes: ‘The pace picked up as Banting and Best began adjusting extract . . . On December 2, 1921 . . . the injections threw the longevity dog, number 27, into repeated convulsions. . . . It finally died, killed by the extract.’ (1). It is acknowledged that the organism has an intricate control mechanism to regulate glycemic levels within a narrow range; insulin as the hypoglycemic agent, and an array of mechanisms as a control against potentially fatal hypoglycemia. The central nervous system (CNS) plays a major role in sensing glucopenia and triggering hormone release during imminent hypoglycemia (2–4). As previous studies have demonstrated, selective perfusion of the cranial arteries with glucose abrogate counterregulation elicited by insulin-induced hypoglycemia, but hepatic glucoreceptors have also been reported to sense hypoglycemia and to activate the sympathoadrenal system (5). This mechanism is regarded to be secondary to the dominant role of the CNS. Several lines of evidence localize the specific region which is responsible for activation of counterregulatory mechanisms to the ventromedial hypothalamus (VMH): focal lesioning of this region abolishes the hormonal response to systemic hypoglycemia (6) and production of local hypoglycemia by perfusion of 2-deoxy-glucose into the VMH is able to trigger the release of counterregulatory hormones despite systemic normoglycemia (7). Alternatively one may ask: when peripheral hypoglycemia is induced by insulin, does continued supply of glucose to the VMH prevent the peripheral neurohumoral counterregulatory response? This question has been studied in a recent and most remarkable piece of work in which the authors were able to demonstrate the central role of the VMH in sensing and responding to hypoglycemia (8). Indeed, they showed that in awake rats, local perfusion of glucose to the VMH by a microdialysis technique blocks counterregulation during systemic hypoglycemia (8). Most of the counterregulatory responses were abrogated. At this point it is important to note that counterregulatory mechanisms normally come into play well before hypoglycemia ensues (4), such that it may be assumed that the VMH is usually active in physiologic situations. Glucagon – an important counterregulatory hormone – is an exception since it appears to be regulated normally regardless of the state of the VMH, suggesting that ambient glucose levels directly or indirectly regulate glucagon secretion independent of the above mentioned mechanisms. Let us now turn to the pathophysiology of hypoglycemia when it arises from prolonged fasting or strenuous exercise. During these situations circulating ketone bodies and lactate levels increase severalfold. In both situations certain signs and symptoms of hypoglycemia are diminished. In experimental situations, hyperketonemia and hyperlactacidemia lowered responses to hypoglycemia in humans (9–11). One of these studies reported that lactate infusions protect cerebral function during hypoglycemia suggesting a potential therapeutic application of lactate during hypoglycemia in patients with insulin overdosage (11). Another important finding of these studies is that, during glucopenia, ketone bodies and lactate can serve as an immediate energy substitute to the CNS. Future studies will reveal whether – similar to glucose – local infusion of ketone bodies and lactate to the VMH will abrogate the hormonal response to hypoglycemia. Moreover, the sensing at the molecular level of hypoglycemia and/or adequate alternative energy supplies to the brain remain to be investigated.

Sympathoadrenal system in neuroendocrine control of glucose: mechanisms involved in the liver, pancreas, and adrenal gland under hemorrhagic and hypoglycemic stress.

Glucose homeostasis is maintained by complex neuroendocrine control mechanisms, involving three peripheral organs: the liver, pancreas, and adrenal gland, all of which are under control of the autonomic nervous system. During the past decade, abundant results from various studies on neuroendocrine control of glucose have been accumulated. The principal objective of this review is to provide overviews of basic adrenergic mechanisms closely related to glucose control in the three peripheral organs, and then to discuss the integrated glucoregulatory mechanisms in hemorrhage-induced hypotension and insulin-induced hypoglycemia with special reference to sympathoadrenal control mechanisms. The liver is richly innervated by sympathetic and parasympathetic nerves. The functional implication in glucoregulation of sympathetic nerves has been well-documented, while that of parasympathetic nerves remains less understood. More recently, hepatic glucoreceptors have been postulated to be coupled with capsaicin-sensitive afferent nerves, conveying sensory signals of blood glucose concentration to the central nervous system. The pancreas is also richly supplied by the autonomic nervous system. Besides the well documented adrenergic and cholinergic mechanisms, the potential implication of peptidergic neurotransmission by neuropeptide Y and neuromodulation by galanin has recently been postulated in the endocrine secretory function. Presynaptic interactions of these putative peptidergic neurotransmitters with the classic transmitters, noradrenaline and acetylcholine, in the pancreas remain to be clarified. It may be of particular interest that it was vagus nerve stimulation that caused a dominant release of neuropeptide Y over that caused by sympathetic nerve stimulation in the pig pancreas. The adrenal medulla receives its main nerve supply from the greater and lesser splanchnic nerves. Adrenal medullary catecholamine secretion appears to be regulated by three distinct local mechanisms: adrenoceptor-mediated, dihydropyridine-sensitive Ca2+ channel-mediated, and capsaicin-sensitive sensory nerve-mediated mechanisms. In response to hemorrhagic hypotension and insulin-induced hypoglycemia, the sympathoadrenal system is activated resulting in increases of adrenal catecholamine and pancreatic glucagon secretions, both of which are significantly implicated in glucoregulatory mechanisms. An increase in sympathetic nerve activity occurs in the liver during hemorrhagic hypotension and is also likely to occur in the pancreas in response to insulin-induced hypoglycemia. The functional implication of hepatic and central glucoreceptors has been suggested in the increased secretion of glucose counterregulatory hormones, particularly catecholamines and glucagon.

Importance of Hepatic Glucoreceptors in Sympathoadrenal Response to Hypoglycemia

To ascertain whether hepatic glucoreceptors are important to hypoglycemic counterregulation, a localized euglycemic clamp was employed across the liver during general hypoglycemia. Dogs were infused peripherally with insulin (18-21 pmol.kg-1.min-1) for 150 min to induce systemic hypoglycemia. During the liver-clamp (LC) protocol, glucose was infused via the portal vein to maintain euglycemia at the liver. In control experiments, i.e., matched infusion (MI), glucose was infused peripherally at a rate determined to yield similar arterial glycemia levels in the two protocols. Arterial glucose concentrations were not different between protocols during the final hour of insulin infusion (3.26 +/- 0.21 and 3.25 +/- 0.21 mM during LC and MI, respectively; P = 0.91). Calculated hepatic glucose concentrations during the same period were significantly higher for LC (5.22 +/- 0.23 mM) than for MI (3.25 +/- 0.21 mM). During MI, both epinephrine and norepinephrine rose significantly from basal values of 562 +/- 87 pM and 1.21 +/- 0.19 nM to plateaus of 3691 +/- 1097 pM (P = 0.0001) and 2.38 +/- 0.35 nM (P = 0.0002), respectively. However, during LC, the elevation in epinephrine was suppressed by 42 +/- 8% (P = 0.015) relative to MI. Six of seven animals demonstrated a suppression in the norepinephrine response, averaging 32 +/- 13% (NS, P = 0.068). The glucagon response to hypoglycemia was unaffected by the level of hepatic glycemia. Hepatic hypoglycemia is essential to produce the full sympathoadrenal response to insulin-induced hypoglycemia.

Effects of selective hepatic vagotomy on running endurance in rats

The liver, through the afferent ways of the vagus hepatic nerve, may influence metabolic adaptations during exercise. This study assesses the functional significance of this hepatic innervation by determining the effect of a selective hepatic vagotomy (HV) on running endurance time during submaximal activity in rats subjected to an overnight 50% food restriction. The time to exhaustion was similar for the groups of HV and sham-operated (SHM) rats [66 +/- 15 vs. 64 +/- 21 (SD) min]. The HV group was associated with higher resting levels (P less than 0.05) of hepatic glycogen and plasma glucose. No significant differences were observed between HV and SHM rats at rest and after exercise for muscle glycogen, free fatty acids, insulin, glucagon, and lactate concentrations. These data indicate that if hepatic glucoreceptors do exist and contribute to the metabolic regulation of exercise, their functional significance is secondary to more important regulatory mechanisms.

The effect of portal infusions of epinephrine on ingestion, plasma glucose and insulin in dogs

Preabsorptive satiety has been hypothesized to occur as the result of food activating oral and gastrointestinal receptors that cause the release of catecholamines in the liver. The catecholamines were then proposed to hyperpolarize hepatic glucoreceptors and produce satiety. In the present study the hepatic portal vein was chronically cannulated in six mongrel dogs. Upon recovery the dogs were infused, over three minutes, with either saline or epinephrine (0.83 and 1.5 μg/kg b.wt.). Infusions ended 10 minutes prior to the animals' daily one-hour feeding period. The epinephrine infusions resulted in physiological increases in plasma glucose and insulin, but did not inhibit food consumption. The animals were next prefed 20% of their normal daily food intake 30 minutes prior to infusion of epinephrine at the above noted doses. Again plasma glucose and insulin increased, but food consumption was not affected. These data show that epinephrine infusions which produce physiological changes in plasma glucose and insulin do not alter feeding behavior of mongrel dogs. These findings are in agreement with previous data that question the physiological importance of the preabsorptive catecholamine satiety hypothesis.

Hepatic branch vagotomy attenuates the feeding response to 2‐deoxy‐D‐glucose in rats

The effect of hepatic branch vagotomy on the feeding response induced in rats by intraperitoneally injected 2-deoxy-D-glucose (2-DG) was tested. Injections were given 1 h after onset of the dark phase, and immediately [corrected] after the rats had ingested a meal. 2-DG produced a smaller feeding response in hepatic branch-vagotomized rats compared with that in sham-vagotomized rats. This finding suggests that hepatic glucoreceptors with vagal afferent fibres are involved in the feeding response to glucose deprivation.

The effect of portal and jugular infused glucose, mannitol and saline on food intake in dogs

Hepatic glucoreceptors have been hypothesized to have an important role in determining normal hunger and satiety. In the present study 23 dogs were fitted with chronic hepatic portal and jugular vein cannulas. The dogs were fed for 1 hr/day. On infusion days (total of 318 infusions) the animals were infused into the portal or jugular veins with a 30% glucose solution (2.4 or 3.6 g/kg, b.wt.), 0.9% NaCl as a volume control or 30% mannitol as an osmotic control and then fed 10 minutes later. The data showed that the dog's food consumption was similar after they received glucose or the appropriate control infusion regardless of the infusion site. Some dogs had blood samples taken for glucose and insulin determinations prior to infusion, at the middle and end of infusion, just prior to food presentation and at the end of the feeding period. Saline and mannitol infusions did not alter plasma glucose or insulin concentrations; whereas there were marked increases in plasma glucose (6–8 x) and insulin (18–19 x) following glucose infusions. Postinfusions glucose values indicated approximately 72% of the infused dose glucose (∼43 g) had left the plasma prior to food presentation. Despite the large increases in plasma glucose and insulin, as well as glucose storage and/or oxidation, the dogs consumed amounts of food similar to that eaten after control infusions. Similarly, prefeeding the dogs 20% of their average daily intake prior to infusion did not alter the animals subsequent intake. These data are in agreement with earlier work from our laboratory and question the role of the hypothesized hepatic glucose satiety receptors.

Effect of hepatic vagotomy on postexercise substrate levels in food-restricted rats.

The metabolic effects of a selective hepatic vagotomy (HV) were investigated at rest and immediately after a 50-min exercise period (26 m/min, 0% grade) in rats subjected to an overnight 50% food restriction. This dietary restriction reduced liver glycogen content to 50% of normal resting concentrations (2.2-2.8 g/100 g). No significant differences between HV and sham-operated rats were found in resting and exercising beta-hydroxybutyrate, glucose, glycerol, and insulin concentrations. Postexercise liver glycogen concentrations were reduced to approximately 1.0 g/100 g in both HV and sham-operated groups. This decrease was associated with significantly (P less than 0.01) lower postexercise glycogen levels in the soleus muscle of HV rats (2.6 times) along with higher plasma free fatty acid concentrations (P less than 0.01). These data provide evidence that HV combined with a progressive decrease in liver glycogen content may influence substrate regulation during exercise. They also support the concept of the existence of hepatic glucoreceptors responsive to a decrease in liver glycogen content.

Glucose Sensors in Viscera and Control of Blood Glucose Level

In addition to the well-known glucose-responsive neurons in the hypothalamus, recent studies of sensory signals from the visceral area have brought us a new understanding of the mechanisms that control the blood glucose level. The activity of efferent fibres to the pancreas and the liver is precisely modulated, not only by central hypothalamic glucoreceptors but also by peripheral (hepatic and intestinal) glucoreceptors.

Convergence of sensory information from abdominal viscera in the rat brain stem.

This study was carried out to establish whether there was convergence of sensory information in the rat brain stem stimulated by physiological activation of gastric mechanoreceptors and hepatic glucoreceptors. Extracellular recordings were made from single neurons in the region of the dorsal vagal nucleus and nucleus of the solitary tract in the medulla. The responses of these neurons to gastric distension, hepatic portal vein perfusion of isotonic D-glucose, and hepatic portal vein infusion of isotonic saline were studied. Fifty-six neurons were studied; it was found that there was no significant difference in the proportion of neurons responding to gastric distension compared with the number responding to either form of hepatic stimulation. In 20 neurons (all 3 types of stimulation were tested on the same neuron), both excitation and inhibition were observed with both forms of visceral stimulation. Of the seven of these neurons that responded to hepatic portal vein infusion, four of them also had an input from gastric mechanoreceptors. Only three of the neurons that responded to hepatic stimulation showed a specific response to hepatic glucose perfusion; in the remainder a component of the response was due to the infusion of the volume itself. The results from these experiments have demonstrated an apparently weak functional synaptic projection carried by hepatic vagal afferents, particularly those responding to changes in portal glucose concentration, which may indicate a rather diffuse and nonspecific sensory system in the liver. These results have also demonstrated the convergence onto neurons in the brain stem of information from gastric and hepatic enteroceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The hepatic vagus nerve and the neural regulation of insulin secretion.

Despite considerable evidence that vagal neural efferent pathways between brainstem and pancreatic islets may alter the secretion of insulin, afferent pathways which might affect this system have received little attention. In the present work we have examined the effects on plasma insulin concentration of several treatments designed to alter the neural activity of the hepatic vagus nerve, a major afferent pathway between the liver and the medulla. The hepatic vagus nerve was acutely sectioned or stimulated electrically in separate experiments in rats. In a third experiment, glucose or 3-O-methylglucose was given ip to stimulate or inhibit, respectively, the hypothetical hepatic glucoreceptors. The effects of these treatments were assessed by measuring arterial or portal plasma insulin concentrations. Anesthesia and its possible secondary inhibitory effects on insulin secretion were avoided by a spinal sectioning of the rats in the cervical region, before experimentation. Acute section of the hepatic vagus nerve between the liver and the main anterior vagal trunk caused an increase in both arterial and portal plasma insulin concentrations. Stimulation of the central end of the nerve suppressed the concentration of the hormone in both the arterial and portal plasma relative to sham-stimulated controls. Section of the celiac vagal branches to the pancreas abolished these changes. Intraperitoneal glucose enhanced arterial insulin more in sham-vagotomized than in hepatic-vagotomized rats. After 3-O-methylglucose was given ip, the response was the opposite: insulin rose more in the arterial plasma of the hepatic-vagotomized animals than in those sham vagotomized. These results suggest that the hepatic vagus nerve plays a role in the regulation of insulin secretion. They are consistent with the hypothesis that afferent fibers in this nerve exert a tonic inhibition on the brainstem centers of an efferent vagal pancreatic neuroendocrine system.

Mechanism of sympathetic activation during prolonged physical exercise in dogs. The role of hepatic glucoreceptors.

It seems likely that depletion of body carbohydrates may account for the rise in the sympathetic activity during prolonged exercise, since glucose given during or before exercise reduces the increase in plasma catecholamines. The aim of the present study was to find out whether the increase in plasma noradrenaline (NA) in response to exercise can be reduced by 1. increasing of the amount of carbohydrate available for metabolism without producing hyperinsulinemia and 2. by inhibition of afferent activity from hepatic glucoreceptors. The study was performed on dogs which exercised whilst receiving either the intravenous fructose infusion (2.2 mmol/min) or a slow glucose infusion (0.25 mmol/min) which was given either via the portal or a peripheral vein. Fructose infusion reduced the muscle glycogen depletion during exercise and reduced the increase in plasma NA and glycerol concentrations without altering the blood glucose or insulin levels. The exercise-induced increases in plasma NA and glycerol concentrations were significantly smaller with intraportal than with peripheral glucose infusion but there were no differences between these two cases in the concentration of glucose in the systemic circulation. These findings indicate that the reduction of the plasma NA response to physical effort under conditions of increased carbohydrate availability cannot be attributed to the inhibitory effect of insulin on sympathetic activity and provide evidence for the participation of hepatic glucoreceptors in the control of the sympathetic activity during exercise.

Hepatic glucoreceptors do exist but do not control food intake

Hepatic glucoreceptors do exist but do not control food intake

Cerebral and hepatic glucoreceptors: Assessment of their role in food intake control by the uptake of 3H-2deoxy-D-glucose

The relative contributions of cerebral and hepatic glucoreceptors in the regulation of food intake is estimated on the basis of the distribution of the labelled glucose antimetabolite — 3H-2DG — in selected glucosensitive tissues under conditions in which the non-radioactive 2DG was previously shown to be a highly effective stimulus for the initiation of food intake.

Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs

Total liver denervations were attempted on 5 mongrel dogs. At the same time, the hepatic portal vein was cannulated with a polyethylene cannula which was exteriorized. Five sham operated, cannulated dogs served as controls. Both denervated and sham operated dogs returned to preoperative food intake within 8 days post surgery. After recovery, intraportal infusions of 6 to 25 g of glucose prior to food presentation in 23 hr fasted sham or denervated dogs resulted in no anorexia. The portal vein and jugular vein were cannulated in an additional 4 dogs. Jugular blood samples were taken prior to and after portal infusion of 20 g of glucose in 23 hr fasted dogs. Both jugular blood glucose and insulin concentration increased significantly 1 to 2 min after portal infusion. The dogs were presented with food 3 to 5 min after the cessation of infusion, yet they showed no anorexia. These same 4 dogs were given portal infusions of either 0.5 μg/kg, 1.0 μg/kg or 1.5 μg/kg of adrenaline after a 23 hr fast. When food was presented 10 min after the infusions were stopped, the dogs ate immediately showing no signs of anorexia. These results question the role or the existence of hepatic glucoreceptors in the control of food intake in the dog.

Effects of visceral sympathectomy on 2-deoxy-D-glucose induced eating

The glucose anti-metabolite 2-deoxy-d-glucose (2DG) when infused through the hepatic-portal circulation caused greater food intake with shorter latency to eat than jugular vein infusion when this comparison was made in intact female rabbits. In visceral sympathectomized rabbits hepatic-portal-2DG infusions had little immediate effect on feeding whereas jugular vein infusion of 2DG had a greater effect than in intact rabbits. The results of hepatic-portal 2DG infusions support the existence of hepatic glucoreceptors and their innervation by afferents passing through the visceral sympathetic ganglia. The fact that visceral sympathetomy enhanced food intake after jugular 2DG, which probably differentially activates central glucoreceptors, suggests that CNS glucoreceptors may play an important role in feeding. However, when CNS glucoreceptors are activated by extremes of glucoprivation their effect on feeding may be masked by central sympathetic activation causing inhibition of feeding.

Injection de glucose dans le territoire porte chez l'homme, absence d'alliésthesie négative en réponse à des stimulus sucrés

Two groups of ten human subjects received 30 g or 50 g respectively of glucose injected into the arteria mesenterica superior. Sweet gustatory sensation was explored by presenting a range of solutions. The evolution of hedonic responses before and after intraarterial glucose loads was recorded by asking the subjects to score pleasantness and unpleasantness on a +2, −2 scale. Intraarterial glucose load did not affect the responses. It is concluded that the negative alliesthesia normally occurring after oral and intragastric feeding does not have its origin in hepatic glucoreceptors.

Neurohumoral Coding of Brain Function

I: Molecular Correlates of Brain Function.- The Role of ?-Aminobutyric Acid Metabolism in the Regulation of Cerebral Excitability.- Biochemical Neuranatomy of the Basal Ganglia.- Cyclic AMP and the Inhibition of Cerebellar Purkinje Cells by Noradrenergic Synapses.- Evidence for Cholinergic Transmission in the Cerebral Cortex.- II: Neurohumoral Mechanisms in Basic Physiologic Functions.- Coding of Metabolic Information by Hepatic Glucoreceptors.- Neurochemical Mechanisms of Temperature Regulation and Food Ingestion.- Functional Changes of Synapses.- The Chemical Coding of Aggression in Brain.- Regulation of Hippocampal Information Processing by K+ Release and (K+)o Accumulation: Possible Role in Learning.- III. Neurohumoral Mechanisms in Behavioral Regulation.- to Session III.- Modulatory Effects of Acetylcholine and Catecholamines in the Caudate Nucleus during Motor Conditioning.- The Effects of Drugs and Electrical Stimulation of the Brain on Memory Storage Processes.- Neurohumoral Coding of Sleep by the Physiological Sleep Factor Delta.- The Possible Nature of Sleep Inducing Brain Perfusates: Their Relationship to Seizure Inhibition.- 5-Hydroxyindoleacetic Acid in Cerebrospinal Fluid during Wakefulness, Sleep, and After Electrical Stimulation of Specific Brain Structures.- Modulation of Subcortical Inhibitory Mechanisms by Melatonin.- Interaction of Amine Systems in the Central Nervous System in the Regulation of the States of Vigilance.- IV: Neurohumoral Factors and Mental Disorders.- Comparative Biochemical and Behavioral Studies of Chronic Schizophrenic Patients and Normals.- Phenylethylamine: Possible Role in Depression and Anti-depressive Drug Action.- Neurochemical, Neuroendocrine and Biorhythmic Aspects of Sleep in Man: Relationship to Clinical Pathological Disorders.- The Chemical Coding via the Cholinergic System: Its Organization and Behavioral Implications.- A Model of the Vertebrate Nervous System Based Largely on Disinhibition: A Key Role of the GABA System.- List of Contributors.- Author Index.

The action of adrenergic anorexigenic substances on rats recovered from lateral hypothalamic lesions

Adrenaline had no anorexigenic effect on rats in Stage 2 of recovery from bilateral lateral hypothalamic lesions at which time they were already eating wet palatable food but still incapable of caloric regulation. Once caloric regulation was recovered (Stages 3 and 4), and body weight was maintained without tube feeding, the anorexigenic effect of adrenaline reappeared. In contrast, in the recovered laterals (Stages 3 and 4) amphetamine produced less anorexia than in the normal rats and the hyperphagic effect of insulin was absent. There is evidence that adrenaline produces its effect via the hepatic glucoreceptors whose normal central pathways would traverse the lateral hypothalamus. Therefore, the lesion to these pathways might be, at least in part, cause of the aphagic syndrome and of the lack of adrenaline anorexigenic effect. Compensatory pathways that would become functional during the recovery process might account, at least in part, for the recovery of regulation and reappearance of adrenaline anorexia. On the other hand, amphetamine and hypoglycemia (insulin) might produce their effects on food intake by a direct action upon hypothalamic centers, and, therefore, the lateral lesions affect them permanently, reducing amphetamine anorexia and eliminating insulin hyperphagia.