Bang-bang control of feeding: role of hypothalamic and satiety signals

Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on–off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro–hormonal data, and both short-term (meals) and long-term (eating-rate regulation) behavioral data.     

Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation

The current epidemic of obesity and its associated metabolic syndromes impose unprecedented challenges to our society. Despite intensive research on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of the leptin neural pathway in the hypothalamus in the regulation of body weight homeostasis. Important hypothalamic neuropeptides have been identified as critical neurotransmitters from leptin-sensitive neurons to mediate leptin action. Recent research advance has significantly expanded the list of neurotransmitters involved in body weight-regulating neural pathways, including fast-acting neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate. Given the limited knowledge on the leptin neural pathway for body weight homeostasis, understanding the function of neurotransmitters released from key neurons for energy balance regulation is essential for delineating leptin neural pathway and eventually for designing effective therapeutic drugs against the obesity epidemic.     

Further evidence of the inhibitory role of perifornical hypothalamic beta-adrenergic receptors in the feeding behaviour of hungry rats

The reduction of food intake in hungry rats induced by salbutamol (10 mg/kg/i.p.) was prevented by IPS 339 (5 mg/kg, i.p.) a selective beta 2 adrenergic antagonist, but not by metoprolol (10 mg/kg i.p.), a blocker of beta 1 adrenergic receptors. Similarly, bilateral injections of IPS 339 (32 micrograms/1 microliter) but not metoprolol (80 micrograms/1 microliter) in the perifornical hypothalamic area completely antagonized the anorectic effect of intraperitoneal salbutamol, suggesting an involvement of beta 2 adrenergic receptors in this brain area. Clenbuterol, a beta 2 adrenergic agonist which readily crosses the blood-brain barrier, was 10-100 times more potent than salbutamol in inhibiting feeding consumption of deprived rats when injected intraperitoneally and this effect was also selectively antagonized by pretreatment with IPS 339. Neither IPS 339 nor metoprolol injected in the perifornical hypothalamus significantly modified the anorectic effect of diethylpropion (5 mg/kg i.p.) whereas it was partially prevented by intraperifornical injection of 1-propranolol (52 micrograms/2 microliter), a non-selective beta antagonist, suggesting that both beta 1 and beta 2 adrenergic receptors in the hypothalamus contribute to the mechanism by which diethylpropion causes anorexia.     

Role of AgRP on Ghrelin-induced feeding in the hypothalamic paraventricular nucleus

MT II, agonist for MC3/4-Rs, inhibited Ghrelin's orexigenic effect in the paraventricular nucleus of the hypothalamus (PVN). To further investigate the role of the melanocortin system as mediator of ghrelin's orexigenic actions, we explored the involvement of AgRP in Ghrelin's orexigenic effect by testing the effect on food intake after their co-administration in the PVN, during the light and dark phases of feeding in rats. During both the phases of feeding, co-administration of Ghrelin with either AgRP 50 or AgRP 100 pmol into the PVN did not produce a synergistic effect on the food intake, suggesting that ghrelin induction of feeding occurs by recruiting Agrp as one of the obligatory mediators of its orexigenic effect.     

Gamma-protocadherins regulate the functional integrity of hypothalamic feeding circuitry in mice

The hypothalamic neuronal circuits that modulate energy homeostasis become mature and functional during early postnatal life. However, the molecular mechanism underlying this developmental process remains largely unknown. Here we use a mouse genetic approach to investigate the role of gamma-protocadherins (Pcdh-γs) in hypothalamic neuronal circuits. First, we show that rat insulin promoter (RIP)-Cre conditional knockout mice lacking Pcdh-γs in a broad subset of hypothalamic neurons are obese and hyperphagic. Second, specific deletion of Pcdh-γs in anorexigenic proopiomelanocortin (POMC) expressing neurons also leads to obesity. Using cell lineage tracing, we show that POMC and RIP-Cre expressing neurons do not overlap but interact with each other in the hypothalamus. Moreover, excitatory synaptic inputs are reduced in Pcdh-γ deficient POMC neurons. Genetic evidence from both knockout models shows that Pcdh-γs can regulate POMC neuronal function autonomously and non-autonomously through cell-cell interaction. Taken together, our data demonstrate that Pcdh-γs regulate the formation and functional integrity of hypothalamic feeding circuitry in mice.     

Weighing in on ubiquitin: the expanding role of mass-spectrometry-based proteomics

Mass-spectrometry-based proteomics has become an essential tool for the qualitative and quantitative analysis of cellular systems. The biochemical complexity and functional diversity of the ubiquitin system are well suited to proteomic studies. This review summarizes advances involving the identification of ubiquitinated proteins, the elucidation of ubiquitin-modification sites and the determination of polyubiquitin chain linkages, as well as offering a perspective on the application of emerging technologies for mechanistic and functional studies of protein ubiquitination.     

Agouti-related protein in the hypothalamic paraventricular nucleus: effect on feeding

Agouti-related protein (Agrp) is an endogenous melanocortin-4 receptor antagonist implicated in the regulation of food intake. Effects of Agrp on feeding under varying conditions were investigated. Agrp (10 to 100 pmol) was injected into the hypothalamic paraventricular nucleus of satiated (a.m. and p.m. injections) and food-deprived rats, or was co-administered with 117 pmol Neuropeptide Y (NPY). Agrp significantly stimulated light-phase feeding by 24 h post-injection. However, Agrp stimulated dark-phase and deprivation-induced feeding by 4 and 2 h, respectively. Animals receiving NPY and Agrp consumed more than animals receiving either peptide alone, the effect remaining by 24 h.     

Regulatory role of monoamine neurotransmitters in Saccharomyces cerevisiae cells

Proliferation of Saccharomyces cerevisiae EPF cells on solid maltose-peptone-yeast extract (MPY) medium was stimulated by the addition of monoamine neurotransmitters. Dopamine turned out to be the most efficient among them: it caused approximately 8-fold growth stimulation at 1 microM concentration. The dopamine effect was partly mimicked by apomorphine, a dopamine receptor agonist. Serotonin and histamine produced less significant (1.5-2-fold) effects, and norepinephrine virtually failed to stimulate yeast culture growth. These data point to a specific, apparently receptor-dependent mode of action of the tested neurotransmitters on S. cerevisiae cells. Using high efficiency liquid chromatography, serotonin, catecholamines (dopamine and norepinephrine), catecholamines precursor dioxyphenylamine, and oxidized amine products (homovanilic acid, dihydrophenylacetic acid, and 5-hydroxyindolacetic acid) were established to be accumulated in yeast cells up to (sub)micromolar concentrations without their release into the culture fluid supernatant (CSF). The results obtained suggest that the tested amine neurotransmitters and related compounds do not serve as autoregulators in the yeast population. Nevertheless, they may be involved in the regulation of yeast population development by other ecosystem components.     

Leptin leads hypothalamic feeding circuits in a new direction

A decade ago, leptin (from the greek lepto meaning 'thin') was identified as the product of the ob gene.1 This adipocyte-derived hormone was found to suppress feeding and stimulate thermogenesis, and was thus proposed as a mediator in a negative feedback loop that controls body adiposity. This discovery led to a rapid revolution in the understanding of neurobiological mechanisms regulating obesity. However, while leptin's first life was as an adipostat, it is now known to have a wide range of additional neuroendocrine, metabolic and behavioural functions in the CNS and periphery. Remarkably, the pleiotropic nature of the hormone continues to be extended with the recent publication of two papers that expand on leptin's neurobiological actions in the CNS.2,3 They indicate novel regulatory roles for the hormone in both synaptic plasticity and axon guidance. Crucially, in light of the rising incidence of obesity in modern society, both of the studies reveal leptin-mediated links between nutrition and neurodevelopment, findings that have further implications for leptin's role in the regulation of energy homeostasis.     

The role of amino acid neurotransmitters in the descending control of electroreception

The roles of amino acid neurotransmitters in determining the processing characteristics of the electrosensory lateral line lobe (ELL) in Apteronotus leptorhynchus were investigated by studying the responses of ELL output neurons to pressure ejection of various neurotransmitter agonists and antagonists alone and in combination with simple electrosensory stimuli.

1. Pressure ejection of L-glutamate into the ELL dorsal molecular layer caused either excitation or inhibition of ELL efferent neurons (pyramidal cells). The sign of these responses reversed with changes in the position of the pressure pipette. Histological verification of drug ejection sites relative to recorded cells and diffusion estimates indicate that excitatory and inhibitory responses result from glutamate activation of pyramidal cells and of inhibitory interneurons, respectively.
2. ELL output cells respond to both NMDA and non-NMDA glutamate agonists and the responses are attenuated by co-ejection of specific antagonists indicating that both AMPA/kainate and NMDA receptors exist on pyramidal cell apical dendrites.
3. Gamma-aminobutyric acid inhibits basilar and nonbasilar pyramidal cells when ejected near their apical dendrites and disinhibits them when ejected near surrounding inhibitory interneurons confirming the presence of GABA receptors on these cell types.
4. An NMDA antagonist did not alter pyramidal cell responses to electrosensory stimuli but a non-NMDA antagonist altered both responses to the stimuli and firing frequency shortly following stimulus cessation.

     

Cholecystokinin acts on the hypothalamic “noradrenergic system” involved in feeding

In male long Evans rats, microinjection cannulae were stereotaxically positioned to rest in sites in the preoptic area and medial hypothalamus. After the rats were satiated on wet mash, norepinephrine (NE) was infused in a dose of 2.5 μg and a volume of 0.75 μl into these diencephalic sites. At loci in six animals, NE evoked spontaneous feeding of 5.0 gms or more of wet mash. Cholecystokinin (CCK) infused prior to the NE microinjection either intraperitoneally (0.5–1.0 μg/kg) or at the NE-sensitive hypothalamic sites (75–150 ng) significantly attentuated or blocked the rat's feeding response to NE. The intake of water was unaffected by CCK in both instances. Thus, CCK may act on the diencephalic noradrenergic feeding system indirectly, through vagal afferent pathways, or directly within the animal's hypothalamus.     

The role of tanycytes in hypothalamic glucosensing

Tanycytes are elongated hypothalamic glial cells that cover the basal walls of the third ventricle; their apical regions contact the cerebrospinal fluid (CSF), and their processes reach hypothalamic neuronal nuclei that control the energy status of an organism. These nuclei maintain the balance between energy expenditure and intake, integrating several peripheral signals and triggering cellular responses that modify the feeding behaviour and peripheral glucose homeostasis. One of the most important and well‐studied signals that control this process is glucose; however, the mechanism by which this molecule is sensed remains unknown. We along with others have proposed that tanycytes play a key role in this process, transducing changes in CSF glucose concentration to the neurons that control energy status. Recent studies have demonstrated the expression and function of monocarboxylate transporters and canonical pancreatic β cell glucose sensing molecules, including glucose transporter 2 and glucokinase, in tanycytes. These and other data, which will be discussed in this review, suggest that hypothalamic glucosensing is mediated through a metabolic interaction between tanycytes and neurons through lactate. This article will summarize the recent evidence that supports the importance of tanycytes in hypothalamic glucosensing, and discuss the possible mechanisms involved in this process. Finally, it is important to highlight that a detailed analysis of this mechanism could represent an opportunity to understand the evolution of associated pathologies, including diabetes and obesity, and identify new candidates for therapeutic intervention.     

Muscimol induced feeding: A model to study the hypothalamic regulation of appetite

Intraventricular administration of the GABA agonist, muscimol, reliably induces feeding in sated rats in a dose dependent manner over a range from 50 to 500 ng. We used this pharmacological stimulant of appetite to examine the interrelationships of the peptides and monoamines involved in the hypothalamic regulation of appetite. Eating induced by muscimol (500 ng ICV) was suppressed by the opiate antagonist, naloxone; the dopamine antagonist, haloperidol; the cholinergic antagonist, atropine and by calcitonin. We could demonstrate no effect of thyrotropin releasing hormone or its metabolite histidyl-proline diketopiperazine or cholecystokinin-octapeptide, bombesin, isoproterenol, or phentolamine in doses known to suppress appetite. Based on these experimental results we propose a model of intrahypothalamic appetite regulation.     

The role of the neurotransmitters acetylcholine and noradrenaline in the pathogenesis of stress ulcers

1. Adrenergic and cholinergic mechanisms seem to be involved in the pathogenesis of stress ulcers.2. In this study, gastric ulcers were induced in rats by immobilization and cold. Prior intraperitoneal administration of both anticholinergic (atropine) as well as α-blocking medication (phenoxybenzamine) produced a very significant decrease in stress ulcers.3. Additionally, using the technique of continuous intravenous perfusion in rats, acetylcholine was shown to have a gastric ulcerogenic effect, in contrast to noradrenaline.4. It is concluded that acetylcholine is the peripheral mediator in stress ulcers, while noradrenaline intervenes at the encephalic level in stress ulcer pathogenesis.     

The role of the ventromedial hypothalamic area in periprandial glucoregulation

There is a great deal of evidence that the ventromedial hypothalamic area (VMH) plays a significant role in glucoregulation. The present review synthesizes new and existing data in a coherent model of a hypothalamic glucoregulatory control system whose function is to stabilize blood glucose levels in the face of discontinuous exogenous supply attendant upon meal-feeding. Evidence is arrayed which suggest the VMH is critical in initiating the anticipatory insulin secretion in advance of the meal-related rise in blood-borne nutrients; that insulin rise acts as a messenger to the brain to reduce both CNS glucose utilization and endogenous glucose production in anticipation of the prandial glucose rise; that the VMH suppresses the reactive phase of insulin secretion which occurs in response to rising blood borne nutrients and finally that the VMH acts to restore endogenous production postprandially to ensure a smooth transition from use of exogenous, meal-derived energy back to endogenous stores. The net effect of this VMH modulation would be minimal periprandial glycemic perturbation. Implications of the model for diabetes and weight regulation are discussed.     

The role of hypothalamic malonyl-CoA in energy homeostasis

Energy balance is monitored by hypothalamic neurons that respond to peripheral hormonal and afferent neural signals that sense energy status. Recent physiologic, pharmacologic, and genetic evidence has implicated malonyl-CoA, an intermediate in fatty acid synthesis, as a regulatory component of this energy-sensing system. The level of malonyl-CoA in the hypothalamus is dynamically regulated by fasting and feeding, which alter subsequent feeding behavior. Fatty acid synthase (FAS) inhibitors, administered systemically or intracerebroventricularly to lean or obese mice, increase hypothalamic malonyl-CoA leading to the suppression of food intake. Conversely, lowering malonyl-CoA with an acetyl-CoA carboxylase (ACC) inhibitor or by the ectopic expression of malonyl-CoA decarboxylase in the hypothalamus increases food intake and reverses inhibition by FAS inhibitors. Physiologically, the level of hypothalamic malonyl-CoA appears to be determined through phosphorylation/dephosphorylation of ACC by AMP kinase in response to changes in the AMP/ATP ratio, an indicator of energy status. Recent evidence suggests that the brain-specific carnitine:palmitoyl-CoA transferase-1 (CPT1c) may be a regulated target of malonyl-CoA that relays the "malonyl-CoA signal" in hypothalamic neurons that express the orexigenic and anorexigenic neuropeptides that regulate food intake and peripheral energy expenditure. Together these findings support a role for malonyl-CoA as an intermediary in the control of energy homeostasis.