Gastric control of food intake

Inhibition of gastric emptying leads to enhanced satiety and this mechanism may contribute to the undereating observed after administration of cholecystokinin (CCK) and fenfluramine, and in patients with anorexia nervosa. Pyloric smooth muscle bears specific CCK receptors and the evidence suggests that a major site of action for CCK satiety is in the periphery. CCK receptors are widespread in the neonatal rat stomach but not in the brain and over the first two weeks of life binding in the stomach decreases and that in the brain increases. This and the finding that independent ingestion as well as gastric emptying are inhibited by CCK at birth suggest the stomach as its likely site of action in the neonatal rat. Fenfluramine inhibits feeding in animals and in patients with bulimia nervosa. In monkeys, fenfluramine inhibits gastric emptying and this action correlates with its feeding inhibition. Patients with anorexia nervosa who are acutely starving and rats maintained on a restricted diet have delayed gastric emptying. Anorexic patients showed abnormal reporting of both hunger and satiety, and, together with those with bulimia nervosa, often associated gastric contents with symptoms of eating disorder, indicating disturbed interpretation of gastric signals.     

Visceral factors in the control of food intake

Some years ago, we reported that the increased blood intake of hypoglycemic rats was inhibited by the intravenous infusion of fructose, a sugar that cannot cross the blood-brain barrier and nourish cerebral chemoreceptors. More recent experiments therefore have focused on visceral factors in the control of food intake. Three observations have been emphasized in this review. First, we found that gastric emptying was increased during insulin-induced hypoglycemia, and that this effect also was eliminated by administration of fructose. Hepatic vagotomy abolished both this effect of fructose on gastric emptying and its effect on food intake. Second, we found that in rats with severe diabetes, the rate of gastric emptying did decrease in proportion to increasing concentration of an administered glucose load, as it does in intact rats, but calories emptied more rapidly than normal regardless of the concentration of the load. Third, we found that rats with varying degrees of streptozotocin-induced damage to the pancreas ate more food than intact rats did after an overnight fast, and that individual intakes were proportional to the induced glucose intolerance. The increased eating took the form of shorter intermeal intervals, as if the initial postfast meal did not remain satiating for a normal amount of time. These and other findings suggest that food intake is controlled in part by satiety signals apparently related to the delivery of utilizable calories plus insulin to the liver. These signals also seem to affect gastric emptying and thereby might influence other satiety signals related to gastric distention.     

Role of bombesin-related peptides in the control of food intake

In 1970, Erspamer et al.(1,14)isolated and characterized the tetradecapeptide bombesin (BN) from the skin of amphibian frog Bombina bombina. Subsequently, several BN-like peptides have been identified in mammals, consisting of various forms of gastrin-releasing peptide (GRP) and/or neuromedin B (NMB), together with their distinct receptor subtypes. It has been proposed that BN-related peptides may be released from the gastrointestinal (GI)-tract in response to ingested food, and that they bridge the gut and brain (through neurocrine means) to inhibit further food intake. Conversely, the suppression of release of BN-like peptides at relevant brain nuclei may signal the initiation of a feeding episode. The present review will describe recent pharmacological, molecular, behavioral and physiological experiments, supporting the contention that endogenous BN-related peptides do indeed influence ingestive behaviors. Particular attention is focused on the relationship between these peptides in the peripheral compartment and their impact on central circuits using GRP and/or NMB as transmitters. In addition, however, we will point out various caveats and conundrums that preclude unequivocal conclusions about the precise role(s) of these peptides and their mechanism(s) of action. We conclude that BN-related peptides play an important role in the control of food intake, and may contribute to ingestive disruptions associated with anorexia (anorexia nervosa, AIDS and cancer anorexia), bulimia, obesity and depression. Hence, pharmacological targeting of these systems may be of therapeutic value.     

Role of sensory input in the control of food intake

The role of the sensory input involved in the control of the food intake is briefly reviewed. Signals from mouth and throat, as well as signals from the gastrointestinal tract and the liver, are necessary but none of them are sufficient to induce satiation. The oral cues initiated by the food intake have a dual action on the feeding behavior. They first stimulate the intake in the hungry subjects. They sustain it until the amount of food ingested reaches the level necessary to equilibrate the energy balance. Finally, they participate, with the sensory input from the gastrointestinal tract, in the process inhibiting the food intake. The hedonic hypothesis of the food intake control is an attempt to explain this dual action of the peripheral alimentary analyzer in this homeostatic behavior. It was proposed that the alimentary pleasure or displeasure brought by alimentary stimuli acts as a drive for the food intake behavior. Indeed, in normal human subjects, the affective component of the alimentary sensations is not constant, but depends on the subjects' internal state. From pleasant, in subjects requiring some energy supply for long-term or short-term energy regulation, alimentary sensations become less pleasant or unpleasant in satiated subjects or in overfed subjects. This change of the affective component of a peripheral sensation, according to the internal state, was called: negative alimentary alliesthesia. Alliesthesia is a specific and reproducible phenomenon. It has been shown that the internal signal which induces negative alimentary alliesthesia depends on the carbohydrate concentration into the gastrointestinal tract, mainly into the duodenum. This signal may provide information related to the energy content of the ingested food. The neural or humoral nature of the transmission of this information from the gut to the brain is discussed. A neural link possibly involves the enteric glucidoreceptors recently described. In conclusion, the validity and the limits of the hedonic hypothesis of the food intake is briefly discussed.     

Role of oxytocin in the control of stress and food intake

Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information‐processing cerebral cortex; the cognitive information‐processing prefrontal cortex; reward‐related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress‐related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis‐controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.     

Hypothalamic control of seasonal changes in food intake and body weight

Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections.     

摄食控制的神经体液机制研究进展

从多种神经递质和激素对摄食行为的复杂影响,迷走神经在传递外周和中枢信号中的重要地位,以及中枢神经系统对摄食相关信息的整合作用三个方面,综述了摄食控制神经体液机制研究的一些新进展。     

The role of enterostatin and apolipoprotein AIV on the control of food intake

Procolipase is secreted as a protein consisting of 101 amino acids. In the intestinal lumen, procolipase is activated by trypsin and cleaves to form the active colipase and the pentapeptide from the amino terminus. This pentapeptide is called enterostatin. Pancreatic procolipase synthesis is stimulated by a high-fat diet. A large body of evidence has been gathered in the past decade demonstrating the role of enterostatin in the inhibition of food intake; in particular, fat intake. This aspect of enterostatin will be discussed in this review. Other functions of enterostatin such as the inhibition of insulin secretion, will not. Apolipoprotein AIV is a protein synthesized by the human intestine. Similar to procolipase, the synthesis and secretion of apo AIV are also stimulated by fat absorption. In 1992, Fujimoto et al. first demonstrated that apo AIV is a satiety signal secreted by the small intestine following the ingestion of a lipid meal. Subsequently, this initial observation was followed by a number of studies supporting apo AIV's role in the inhibition of food intake. This review will discuss the role of apo AIV in inhibiting food intake.     

Hypothalamic regulation of food intake

The central regulation of the food intake is organized by a long-loop mechanism involving humoral signals and afferent neuronal pathways to the hypothalamus, obligatory processing in hypothalamic neuronal circuits, and descending commands through vagal and spinal neurons to the body. Receptors sensitive to glucose metabolism, body fat reserves, distension of the stomach, as well as neuropeptide and cannabinoid receptors have been identified and localized in the hypothalamus. Five groups of cells in the hypothalamus--arcuate, paraventricular, ventromedial and dorsomedial nuclei, and the dorsolateral hypothalamic area--contain neurons with either anorexic actions (alpha-MSH, CART peptide, corticotropin-releasing hormone, urocortin III, cholecystokinin, glucagon-like peptides) or that stimulate food intake (neuropeptide Y, agouti-related peptide, orexins, melanin concentrating hormone, galanin). Intrahypothalamic neuronal circuits exist between these peptidergic neurons including the arcuate-paraventricular and arcuate-dorsolateral hypothalamic projections. Circulating substances carrying signals connected to changes in body food homeostasis and energy balance (leptin, ghrelin, insulin, glucose) enter the hypothalamus mainly through the arcuate nucleus. Neurons in the medulla oblongata that express leptin and insulin receptors, as well as neuropeptide mediators project to the hypothalamus. Vica versa, hypothalamic neurons give rise to projections to autonomic centers in the brainstem and the spinal cord with potential for stimulation or inhibition of food intake, energy balance and ingestion behavior.     

Effect of food intake on cardiovascular control in patients with impaired autonomic function

Food intake results in a variety of responses, with the autonomic nervous system playing an important role in maintaining cardiovascular homeostasis. In patients with autonomic failure, who have severe sympathetic impairment, food substantially lowers blood pressure even in the supine position. This is related to a marked increase in splanchnic blood flow, without compensatory changes in the rest of the circulation. Of the food components, glucose causes similar effects to food, while an isosmotic, isocaloric load of the inert carbohydrate, xylose, causes only a small fall in blood pressure. Lipid causes a small, short-lived fall in blood pressure and protein causes minimal change. Insulin appears to contribute to the fall in blood pressure, as bolus injections of insulin (even before ensuing hypoglycaemia), or insulin infusions (with an euglycaemic clamp), when given intravenously lower blood pressure. Other vasodilatatory gut peptides released by food may also play a role. The somatostatin analogue, Octreotide (SMS 201-995), which inhibits the release of a range of peptides, prevents both glucose and food-induced hypotension. Studies of the mechanisms responsible for post-prandial hypotension in autonomic failure continue to provide insight into the relationship between food intake and the hormonal, peptidergic and neural responses which affect the cardiovascular system.     

Does the integrated level of all plasma nutrients control daily food intake?

Studies on two different types of one-way crossed-intestines rats have shown that daily food intake is controlled by either endogenous gut signals or absorbed nutrients and their metabolic consequences, or both. If the amount of incoming ingested food is metered somewhere in the body, this could only occur in the gut or liver. The capacity of the liver to determine the amount of water-soluble nutrient absorbed was assessed by portacaval shunt and found to be inadequate. Infusion of nutrients directly into the bloodstream show that plasma nutrients provide part of the signal that inhibits daily food intake, but that endogenous gut signals must play some role. Insulin, an important hormone in the movement of plasma nutrients into cells, was found to stimulate food intake at low infusion doses. IV nutrients raise the level of plasma nutrients and lower daily food intake, while insulin, which inhibits the release of endogenous fuels and moves exogenous fuels into cells, lowers plasma nutrients and stimulates daily intake. Thus, the integrated level of all plasma nutrients may be a major controller of daily food intake.     

Inhibitory effects of lipopolysaccharide on hypothalamic nuclei implicated in the control of food intake

The arcuate nucleus (Arc) and the lateral hypothalamic area (LHA), two key hypothalamic nuclei regulating feeding behavior, express c-Fos, a marker of neuronal activation in fasted animals. This is reversed by refeeding. In the present study we tested whether an anorectic dose of lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, also inhibits fasting-induced c-Fos expression in these hypothalamic nuclei. This would suggest that they are involved in anorexia during bacterial infections as well. We also studied whether LPS modulates the activity of orexin-A positive (OX+) LHA neurons. Food deprived BALB/c mice were injected with LPS or saline and were sacrificed 4 or 6h later. Four hours after injection, LPS reduced the number of c-Fos positive cells in the Arc and in the LHA, but had no effect on c-Fos in OX+ neurons. Six hours after injection, LPS reduced c-Fos expression in the LHA, both in the OX- and OX+ neurons, but not in the Arc. These results show that LPS modulates neuronal activity in the Arc and LHA similar to feeding-related stimuli, suggesting that the observed effects might contribute to the anorectic effect of LPS. Thus, physiological satiety signals released during refeeding and anorexia during bacterial infection seem to engage similar neuronal substrates.     

Role of glucagon in the control of food intake in zucker obese and lean rats

Although there is strong evidence for glucagon's role in the control of food intake, the essentiality of this role remains in question. In several experiments the feeding responses to glucagon and glucagon antisera were investigated in both Zucker and Sprague-Dawley rats. Intraperitoneal injection of 400 micrograms/kg glucagon decreased 30-min food intake 18% (p less than 0.01) in Zucker lean rats and increased 30-min food intake 16% (NS) in Zucker obese rats, suggesting obese rats are less sensitive. In Sprague-Dawley rats the same dose decreased first meal size 28% (p less than 0.01), indicating that they were more sensitive than Zucker lean rats. Intraperitoneal injection of 400 micrograms/kg glucagon increased plasma glucagon concentrations in the vena cava and the tail vein 150-fold and 10-fold, thus, superphysiological doses may be required to elicit satiety. In contrast, administration of a glucagon antisera increased food intake of Zucker rats for up to 6 hr and increased meal size for 5 hr. The findings suggest that glucagon's role in control of food intake in Zucker obese and lean rats is similar, but the superphysiological glucagon changes which occur with exogenous administration indicate that glucagon may only indirectly elicit satiety.     

Introduction to the reviews on peptides and the control of food intake and body weight

The progress in the identification of peripheral and brain peptides that affect food intake and body weight is discussed in the accompanying 11 reviews. The reviews, succinct and critical, are useful guides to a dispersed literature that began in 1957. As reflected through the prism of these reviews, the field looks like a few small islands of scientific understanding surrounded by a vast sea of uncertain phenomena. This introduction discusses four themes that pervade the reviews. These are: (1) how to establish that an effect of a peptide is a physiological function of the endogenous peptide; (2) the importance of the interactions among peptides, amines and steroids for the central integration that underlies the control of food intake and body weight; (3) the need for simple and convenient generalizations to organize and interpret the apparently endless empirical reports; and (4) the persistent problems that remain untouched by current information, especially dietary-induced obesity and the role of peptides in the neural networks that control spontaneous eating.     

Cholecystokinin: proofs and prospects for involvement in control of food intake and body weight

Evidence that CCK participates in the control of meal size is compelling, but the avenues by which CCK may affect daily food intake and body weight regulation are still uncertain. Although participation of brain CCK in control of food intake is acknowledged, our focus here is on participation of peripheral CCK in the control of food intake. Therefore, in this article we (1) review evidence for CCK's participation in control of meal size, (2) document involvement of CCK-A receptors located on vagal sensory neurons in control of food intake by exogenous and endogenous CCK, (3) point out apparent discrepancies in the experimental record, which auger for non-endocrine sources of CCK and non-vagal sites of CCK action, and (4) summarize recent observations, suggesting mechanisms by which CCK could participate in the control of daily food intake and body weight regulation.     

Brain mechanism underlying food intake regulation

Food intake is precisely regulated in all normal individuals, with a variation of <1%. The hypothalamus is a critical component of the forebrain pathways that regulate long-term energy homeostasis, and it plays a particularly important role in integrating hormonal, neurotransmitter, and nutrient signals. Obese animals fed with high-fat diets show an increase in the inflammatory signals, endoplasmic reticulum stress, and radical oxygen species in the hypothalamus and impairment in the systems regulating food intake. AMP kinase (AMP-activated protein kinase [AMPK]) is a "metabolic sensor" present in a wide variety of organisms, from yeast to mammals. Recent studies have indicated the role of AMPK in hypothalamic neurons in the integration of hormonal, neurotransmitter, and nutrient signals. Furthermore, analysis of genetically engineered mice has revealed that AMPK alters the fatty acid metabolism in the hypothalamic neurons as well as in peripheral tissues, and thereby regulates feeding behavior. Thus, hypothalamic neurons and intracellular signaling pathway that includes AMPK-fatty acid metabolism appear to be the critical components that regulate food intake and body weight.     

Nocistatin inhibits food intake in rats

Nocistatin, a product of the same precursor as nociceptin/orphanin FQ (N/OFQ), has been shown to antagonize effects of N/OFQ. N/OFQ stimulates feeding, most probably by inhibiting activation of neurons containing oxytocin (OT) and vasopressin (VP), peptides considered as satiety factors, and implicated in the development of conditioned taste aversion (CTA). The present study was designed to investigate whether intracerebroventricularly (ICV) injected nocistatin (a) affects deprivation- and N/OFQ-induced feeding, (b) causes CTA, and (c) induces activation of hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, as well as OT and VP neurons present in these regions. C-Fos immunohistochemistry was used as a marker of cellular activation. Nocistatin (1-3 nmol) significantly reduced food intake in deprived rats during the first and second hour post-injection. Doses of 1-3 nmol suppressed N/OFQ-induced feeding. Nocistatin at the highest (3 nmol) dose did not cause CTA. It also did not affect activation of the PVN or SON. In nocistatin-treated animals, the percentage of Fos-positive OT and VP neurons was similar to controls. We conclude that nocistatin antagonizes the influence of N/OFQ on feeding and suppresses deprivation-induced food consumption through mechanisms other than aversion. Nocistatin does not, however, activate the PVN or SON. It does not exert its effects via VP or OT neurons.     

Corticotropin inhibits food intake in rats

The synthetic corticotropin ACTH (1-24) (tetracosactide), injected into a brain lateral ventricle after a 24h starvation period or into the ventromedial hypothalamus during the nocturnal feeding phase, markedly inhibited food intake, in rats. In starved rats, the dose of 4 micrograms/rat was maximally effective and reduced food intake by 76.6% during the first hour after treatment. The same dose, injected into the ventromedial hypothalamus, significantly inhibited food intake also in normally fed rats during the nocturnal phase (58.6% reduction during the 90 minutes of observation). These findings suggest that corticotropin may play a role in the central control of appetite.