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Overview
Signal Transduction Education  
Active Learning Projects - Obesity Project - Team 2    
 
Obesity
Team 1   Team 2   Team 3   Team 4   Team 5   Instructions du Projet
 
1. Regulation of food intake and obesity
2. Messengers involved in the homeostatic regulation of food intake
3. Messengers involved in the hedonic regulation of food intake
4. Signalling mechanisms in the arcuate nucleus and the regulation of food intake
5. Treatment of obesity
Instructions du Projet

active learning, any time, any place and anywhere

Homer-donut

2. Homeostatic regulation of food intake

Summary:
Introduction
Ghrelin
Leptin
Insulin
CCK and PPY
Arcuate nucleus

Auteurs:
Nathalie Authesserre, Guillaume Debourdeau, Eugène Ostrofet, Wilfried Souleyreau.

Introduction

reddot  In this page we deal with the organs, tissues, brain regions and messengers (hormones and neurotransmitters) that are involved in the homeostatic regulation of food intake. We deal with the communication between the digestive tract, pancreas and adipose tissue, on the one hand and the arcuate nucleus in the brain on the other (see figure 1). We focus on the arcuate nucleus because, with respect to regulation of food intake, it is considered the major entry point of hormonal signals. Another important entry point, but this time for neurotransmitters, is the nucleus of the solitary tract (NTS). We describe how the digestive system senses both emptiness and fullness, and sends, respectively, appetite or satiety messages to the brain. We also describe how elevated blood-glucose levels, via the intermediate of the pancreas, as well as elevated levels of fat in adipose tissue, lead to the emission of satiety messages (see figure 1a and table 1). Collectively, these messages provide the brain with a symbolic representation of the feeding status of the organism. The neurons in the arcuate nucleus then send signals towards other regions of the brain giving rise to either a food seeking (orexic) or fasting (anorexic) behaviour. We present a simplified version of what really happens but this description of events should provide a trunk to which new branches can be added.

Homeostasis
From Greek: óμος, hómos, "similar"; and ιστημι, histemi, "standing still"; coined by Walter Bradford Cannon, is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition. Typically used to refer to a living organism. Multiple dynamic equilibrium adjustment and regulation mechanisms make homeostasis possible. Source; Wikepedia

Figure 1 (a) Homeostatic regulation; messengers from the digestive tract (ghrelin, PYY, CCK, leptin), from the pancreas (insulin) and from adipose tissue (leptin) directly converge upon the arcuate nucleus in the hypothalamus or they send messages via the intermediate of afferent neurons of the vagus nerve (which carry receptors for PYY, CKK, leptin and ghrelin). Collectively they provide a symbolic representation of the feeding status of the organism. These messages are then translated into either a food-seeking (orexic) or a fasting (anorexic) behaviour. We ignore the role of the spinal nerves in these webpages. (b) Anatomic location of the arcuate nucleus and the nucleus of the solitary tract (nucleus tractus solitarius or NTS).
Images adapted from: Cellular warriors at the battle of the bulge. Science 2003;299:846-849

Substance Production site Effect (relevant
for feeding)
SwissProt
(human)
ghrelin
(grow)
-stomach (fundus region,
entero-endocrine cells)
- neurons in the hypothalamus
-appetite (orexigenic) Q9UBU3
Receptor
Q92847
anandamide
(endocannabinoide,
(ananda; bliss, delight
+ amide )
small intestine -appetite (orexigenic) Arachidonoyl-
ethanolamide
Receptor
P21554
insulin
(insula; island or islet)
pancreas
(β-cells in islets of Langerhans)
-satiety (anorexigenic)
-glycogen and lipid storage
P01308
Receptor
P08069
leptin
(leptos, thin)
Adipocytes (long term)
Stomach (short term)
-satiety (anorexigenic) P41159
Receptor
P48357
CCK
(cholecystokinin,
“move the bile-sac”)
small intestine -early satiety (anorexigenic)
-release of digestive
enzymes from exocrine
pancreas, bile from
the gallbladder and
H+ from parietal
cells in stomach
P06307
Receptor
P32238
PYY
(peptide tyrosine tyrosine)
ileum and colon -satiety (anorexigenic) P10082
Receptor
P49146

Table 1 Examples of peripheral mediators (messengers) that regulate food intake. Note that only ghrelin and anandamide act as orexigenic substances, all the others provide an anorexigenic signal. Ghrelin, insulin and leptin are treated extensively in this page and in the page of team 4. We have added the SwissProt entry codes so that you can learn as much as you like about these mediators and their receptors “Active learning, any time, any place and anywhere”.

reddot  Next we will describe the sources of mediators involved in the regulation of food intake and then we describe their target, the arcuate nucleus and its nerve cells (neurons) that control feeding or fasting behaviour.

Ghrelin

reddot  Ghrelin is an appetite-inducing peptide hormone. It is secreted by entero-endocrine cells in the fundus region of the stomach. What exactly drives its release from these cells is not known. Some suspect mechanoreceptors that sense the filling state of the stomach. Stretching of the wall may turn off hormone release. It is also produced in small quantities in other parts of the digestive tract, the pancreas and importantly in ghrelin-neurons in the hypothalamus (see below). Ghrelin levels in blood were found to be at their peak just before and at their lowest just after a meal (“post prandial” dip). Important evidence for its role in control of appetite came from the observation that mice lacking either ghrelin or its receptor (GSHR) are protected from diet-induced obesity (although feeding behaviour does not differ from control mice under normal feeding conditions).

reddot  Long term regulation of ghrelin may be influenced by the adiposity state of the organism or other unknown factors. Ghrelin is generally low in obese persons (inhibition by elevated fat storage) and high in people with anorexia nervosa (empty stomach and empty fat stores). It is also unusually high in (obese) people with the Prader-Will syndrome?

reddot  Ghrelin is a peptide hormone, comprising 28 amino-acids (figure 2). It is obtained from a 94 amino-acid precursor named proghrelin. Other products of the prohormone are; des-Gln14-ghrelin (or 27 ghrelin), C-ghrelin and obestatin. About 20% of ghrelin is modified (on Ser-3) by n-octanoic acid (process referred to as octanoylation), through the action of a membrane bound “ghrelin O-acylgransferase” (GOAT). This occurs in the rough-endoplasmic reticulum. Octanoylation is essential for binding to the ghrelin receptor and thus for the induction of appetite (and other functions).

  1. Gardiner J, Bloom S. Ghrelin gets its GOAT. Cell Metabolism 2008;7:193-194 (and references therein).
  2. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005;85:495-522.

Figure 2 (a) An important source of ghrelin is the fundus region of the stomach. The oxyntic mucous contains entero-endocrine cells of different types, of which X/A cells stain most positive for ghrelin. (b) The molecular composition of n-octanoyl-ghrelin. The octanoic acid tail is vital for receptor binding and thus for biological activity of ghrelin.

The discovery of ghrelin
First there was the receptor, discovered as the binding site of synthetic compounds that caused the immediate secretion of growth hormone (GH) from somatotrophic cells of the anterior pituitary. These compounds were developed as potential medicaments aiming to restore body growth (by boosting the production of GH). The “orphan” receptor, lacking a physiological ligand, was named growth hormone-secretagogue receptor (GSHR, of which two splicevariants exist; GSHR1a (full length) and GSHR1b (truncated).

Then there was the ligand which, surprise, was isolated from extracts from the stomach and not, as expected, from the pituitary gland or hypothalamus! Because the newly identified physiological ligand controlled secretion of growth hormone, it was named ghrelin, after ghre, the proto-indo-european root of the word “grow”. Strangely enough, mice lacking either ghrelin or its receptor grow normally.

Only later it was discovered that, when injected in the bloodstream or into cerebral ventricles, it stimulates food intake in rodents. The attentions shifted entirely from studying its role in growth to studying its role in appetite control!
  1. Kojima M et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-660.

reddot  Ghrelin diffuses into the tissues and into the blood. Ghrelin is also detected in the hypothalamus but how it actually reaches this brain region remains unclear. There are two reasons that plead against the idea that stomach-produced ghrelin diffuses into the hypothalamus. Firstly, ghrelin does not easily cross the endothelial cells in the central nervous system because these are tightly associated (tight junctions) and surrounded by pericytes and astrocytes which make passive transport sheer impossible (together these qualities make up the blood-brain-barrier) (figure 3). Active transport has been detected but in the direction of brain-to-blood and not the other way round. Secondly, the appetite-inducing effect of ghrelin is abrogated when the nervus vagus is cut (vagotomy).

Figure 3 The blood brain barrier (endothelial cells + pericytes + astrocyte foot processes) and a lack of active transport prevents diffusion of stomach-produced ghrelin into the hypothalamus.

reddot  The current line of thinking is that the ghrelin produced in the stomach acts on feeding behaviour by inhibiting the activity of the vagus nerve (reducing the discharge of neurotransmitters in the brain). Ghrelin receptors (GHSR) are present on afferent neurons of the vagus nerve. This in turn may cause the local release of ghrelin in the hypothalamus (see figure 13). In the arcuate nucleus, ghrelin stimulates appetite by increasing the activity of orexigenic neurons (the Npy/AgRP/GABA containing neurons) (see figure 13). More information about its mode of action is provided in the web page of team 4.

Sleep loss and weight gain
Sleep restriction in healthy humans is linked to elevated ghrelin and reduced leptin hormone levels, concomitant with an increase in appetite. Suppression of the slow wave sleep (decreasing the “quality” of sleep) leads to a decreased insulin sensitivity and decreased glucose tolerance (diabetes type II symptoms). In other words, sleep, or lack of it, affects the metabolic state of humans and the bottom line is that a good night rest keeps you slim.
  1. Spiegel K et al. Effects of ppor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253-261.
  2. Tasali et al. Slow-wave sleep and and the risk of type II diabetes in humans. Proc Natl Acad Sci USA 2008;105;1044-1049.
Afferent neurons
In the nervous system, afferent neurons (otherwise known as sensory or receptor neurons), carry nerve impulses from receptors or sense organs toward the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons. The opposite activity of direction or flow is efferent. In the nervous system there is a "closed loop" system of sensation, decision, and reactions. This process is carried out through the activity of afferent neurons, interneurons, and efferent neurons. Source; wikipedia
Leptin

reddot  The discovery of leptin (from leptos, thin) started with the discovery of very plump young mice in the V-stock of the Jackson Memorial Laboratory way back in 1949. From breeding data it was concluded that their obese status was due to a recessive gene which they designated by the symbol ob. The recessive gene caused sterility in the homozygote, but there seemed to be no indication of any affect on the life span of the animals during a period of twelve months. Like human obese, the mice develop type II diabetes (see figure 4, images adapted from Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered. 1950;41(12):317-318).

Figure 4 (a) Growth curve of control, “yellow” and obese mice from the V-stock of the Jackson Memorial Laboratory. (b) Control and obese mice at 21 days of age and (c) after 10 months. Images adapted from Ingalls et al. J Hered.1950;41(12):317-318). Much later it was shown that the obese mice lack leptin and thus lack a satiety signal. The “yellow” mice produce an excess of a mutated agouti protein. This normally controls coat colour but, due to aberrant expression, seems to be capable of blocking the α-MSH-mediated satiety signal in the hypothalamus (see below, figure 13).

reddot  When, in 1994, the ob gene was cloned (meaning the gene locus identified and DNA-sequence determined) it was shown that the obese mice carry a nonsense mutation in codon 105 (a nonsense mutation results in a premature stop codon (a nonsense codon), leading to a truncated and usually nonfunctional protein). From this and other data it was concluded that “the ob gene product (the protein) may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot”. A year later it was shown that the protein encoded by the obese gene had weight-reducing effects and was subsequently named leptin.

  1. citation above from Zhang et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432).
  2. Halaas JL et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-546.
  3. Campfield LA et al. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-549).
Mouse models
Progress in the obesity field owes much to fat mice. These were either obtained through natural mutations or through created mutations (targeted mutations) in the laboratory. The genes carrying the mutations, such yellow (ay), obese (ob), diabetes (db), fatty (fa) and tubby (tub), have been cloned and revealed important components of the signalling pathways that regulate food intake (Liebel RL, Chung WK, Chua SC. The molecular genetics of rodent single gene obesities. J Biol Chem 1997:272:31937-31940).

reddot  Leptin is a peptide hormone comprising 167 amino acids. It structure resembles that of long-chain helical cytokines (figure 5) such as granulocyte colony-stimulating factor (G-CSF), leukocyte inhibitory factor (LIF), interleukin-6 (IL-6) or human growth hormone (hGH).


Figure 5 Structure of leptin. Highly conserved amino acids are coloured purple (present in human, gorilla, chimpanzee, orangutan, rhesus monkey, dog, cow, pig, rat and mouse). Pdb entry 1ax8

reddot  Leptin circulates at levels proportional to body fat and white adipose tissue is its main source (figure 6). It enters the central nervous system in proportion to its plasma concentration. Its receptors are found in brain areas involved in regulating food intake and in areas that control energy expenditure. In addition to adipose tissue, it is also detected in brown adipose tissue, placenta (syncytiotrophoblastes), ovaries, skeletal muscle, stomach (in the lower part of fundus glands where ghrelin is produced), mammary epithelial cells, bone marrow, pituitary gland and the liver. How the storage of triglycerides in adipocytes (adiposity) regulates levels of circulating leptin remains unclear.

Adipose tissue; white versus brown
Adipose tissue is an anatomical term for loose connective tissue composed of fat storing cells (adipocytes) (figure 6).
  • White adipose tissue: its main role is to store fatty acids in the form of triglycerides, thus providing the organism with food reserve. Besides this, adipose tissue cushions and thermally insulates the organism. Like any tissue, it also is a source of first messengers (hormones and cytokines) that diffuse into the body. Leptin is produced by adipose tissue. As discussed in the page of team 1, adipose tissue also produces inflammatory cytokines, amongst others TNF-α and IL-6. With an excess of adipose tissue this leads to a chronic mild inflammatory state referred to as the “metabolic syndrome”. In addition, an excess of fully loaded adipocytes causes the release of free fatty acids which may give rise to insulin resistance and thus contributing to the late onset diabetes (type II) in obese people.
  • Brown adipose tissue is much less abundant. It looks brown because of an excess of mitochondria (we suppose that the cytochromes of the electron transport chain provide the brownish colour?). These mitochondria produce little ATP but a lot of heat (thermogenesis). The reason is that they express uncoupling proteins (UCP) in the crista of the inner membrane. These let protons, which are pumped into the inter membrane space by the electron transport chain, re-enter the mitochondrial matrix without engaging the ATP-synthase enzyme. Uncoupling proteins are also expressed in muscle tissue and these may contribute to the energy wasting that keeps you slim, irrespective of aberrant nutritional behaviour (the other side of the coin).
  1. Celi FS. Brown adipose tissue - when it pays to be inefficient. N Engl J Med 2009;360(15):1553-1556 (and references therein).


Figure 6 White adipose tissue and a zoom-up of an adipocyte adjacent to a blood capillary (note the size of the adipocytes which equals 70 micrometers, compared to 7 micrometers of the red blood cell and 10 to 20 micrometers for an ordinary body cell).

reddot  Leptin inhibits appetite by decreasing the activity of orexigenic neurons (Npy/AgRP/GABA containing neurons) and increasing the activity of the anorexigenic neurons (POMC/CART containing neurons) in the hypothalamus (see figure 13). Both populations express the leptin receptor.

Leptin receptor
The leptin receptor is highly expressed in the hypothalamus and it has the characteristics of a cytokine receptor. It is discovered in “diabetic” mice (db), which are fat mice that develop type II diabetes. In short they suffer from a syndrome that resembles morbid human obesity. The mutation in diabetic mice causes abnormal splicing of the mRNA, giving rise to a protein that lacks its cytoplasmic segment. The receptor can bind leptin but cannot signal into the cell (no transduction of the signal from outside to inside). More information about its mode of action is provided in the web page of team 4.
  1. Tartaglia LA et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-1271.
  2. Lee GH et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632-635.
Insulin

reddot  Insulin is a peptide hormone of 51 amino acids derived from a 110 amino acid precursor. The prohormone is cleaved, giving rise to two chains; chain-a and chain–b. These are connected by two disulphide bonds. Insulin is produced by the β-cells of the islets of Langerhans in the pancreas (figure 7).


Figure 7 (a) Composition of pro-insulin and mature insulin. Processing occurs in the Golgi. (b) Insulin is produced by β-cells that reside in the Islets of Langerhans of the pancreas. Glucagon, also involved in glucose metabolism, is produced by α-cells.

reddot  Blood levels of insulin are regulated by the blood glucose concentration (also known as glycemia). Gastric and intestinal absorption of carbohydrates raises blood glucose levels above a steady 70-100 mg/dl. This leads to an increased uptake of glucose in β-cells of the pancreas, which, in reply, release insulin (figure 8). Insulin has a general anabolic effect; it assures removal of glucose from the blood and stimulates its conversion into glycogen (a glucose polymer). When glycogen reaches its saturation point (not more than 300 grams in an adult) insulin contributes to the storage of glucose in adipose tissue in the form of triglycerides (unlimited storage). Insulin in the blood can be regarded as a messenger of plentiness.

reddot  When blood glucose levels drop, insulin secretion seizes. Regulation of blood-glucose levels is taken over by glucagon, also produced by the pancreas. It stimulates the conversion of glycogen in the liver into glucose and causes its release into the blood stream (gluconeogenesis). (NB the glucose in the skeletal muscles cannot enter the bloodstream and are for muscle-use only. The breakdown of muscle glycogen is under control of adrenaline).

Glucose and the brain
Stored glucose, in the form of glycogen, can serve many purposes but an important role is to serve as fuel necessary for the production of ATP by the mitochondria (something that can also very effectively be achieved by fatty acids in case the glycogen stores are depleted). The brain is particularly sensitive to glucose levels as it does not easily use fatty acids for the production of ATP. Blood concentrations at 30 mg/dl or below (hypoglycemia) therefore cause confusion, convulsions and unconsciousness (coma). This is one of the problems diabetics have to deal with because they do not stock the glucose effectively and therefore risk very low levels in between meals.

reddot  Insulin enters the hypothalamus and its receptors are expressed on neurons in the arcuate nucleus. It provides a satiety signal by stimulating the anorexigenic POMC/CART neurons and by inhibiting the orexigenic Npy/AgRP/GABA neurons (see figure 13). Amplifying the insulin signal makes mice resistant to obesity. An excess of adipose tissue renders liver and muscle cells insensitive to insulin (weak intracellular signal) and this may also be true for the neurons in the arcuate nucleus. This leads to a weak satiety signal and may augment food intake. The molecular mechanism by which insulin regulates neurotransmitter release is treated in the web page of team 4.

  1. Elcheby M et al. Increasesd insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999;283:1544-1548
  2. Klaman LD et al. Increased energy expenditure, decreased adiposity and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 2000;20:479-489

Figure 8 Insulin maturation in secretory vesicles of the trans-Golgi network followed by glucose-mediated release from a β-cell in the pancreas. Increased glucose levels in the blood are translated in the β-cells by an increased production of ATP by the mitochondria (more substrate available). Elevated levels of ATP cause the closure of K+ channels and this leads to depolarization of the plasma membrane. As a consequence the Ca2+ conductance increases and the ensuing elevated level of intracellular Ca2+ signals the fusion of secretion vesicles, loaded with insulin, with the plasma membrane. Insulin diffuses into the blood. Important targets are skeletal muscles and the liver. Insulin promotes removal of glucose from the blood (through induction of membrane expression of glucose transporters) and its storage in the form of glycogen. Insulin also reaches the arcuate nucleus and contributes to a fasting behaviour.

Diabetes
Diabetes means siphon (also spelled as syphon), describing the excessive production of urine and the subsequent thirst this provokes. Medically one can siphon in two ways: one where the urine tastes sweet, honey-like, and is thus referred to as diabetes mellitus, the other where the urine is tasteless, named diabetes insipidness. “Sweet siphoning” is the consequence of glucose in the urine shortly after a meal. Due to a lack of insulin (type I diabetes) or due to resistance to insulin (type II diabetes), the glucose that arrives in the blood is not properly stored inside body cells. The excess of glucose spills over in the kidneys and because glucose attracts water, it impedes efficient water retentions from the filtrate, hence an excess of urine. Normally, glucose is reabsorbed in the kidney, before it reaches the bladder, but with such an excess, the transport system simply saturates and the urine gets sweet. In the old days the doctor would taste the urine for diagnosis purpose; nowadays a little glucose indicator stick will tell the bad news.
CCK

reddot  Cholecystokinin is a peptide hormone of 95 amino acids, derived from a 115 precursor (preprocholecystokinin). Ten variants of different sizes are excised from the pro-hormone, giving rise to CCK-58, -39, -33 etc. Which of these 10 variants are important for the regulation of food intake is not clear to us. CCK is produced by I-cells in the mucosal epithelium of the small intestine in response to long fatty acid chains (more than 12 carbons). It is released into the blood at the level of the duodenum. CCK stimulates bile production by the liver, causes release of bile from the gallbladder (hence its name cholecystokinin = move the bile-sac), it stimulates release of enzymes from the (exocrine) pancreas and it decreases the rate of gastric emptying (control of gastric sphincter). Collectively these actions allow optimal digestion of fat and protein in the small intestine.

reddot  CCK also provides a satiety message by having a stimulatory effect on the vagus nerve (increasing the discharge of neurotransmitters in the brain). Vagal afferent neurons (going from the gut to the brain) carry receptors for CCK (CCK1-R). Its stimulatory action is thought to oppose the effect of ghrelin, which inhibits the nervus vagus (see above). Moreover, CCK induces the release of leptin from the stomach and this may enhance the short term satiety signal. We will not return to CCK in the following web pages.

  1. Dockray GJ. Cholecystokinin and gut-brain signalling. Regulatory Peptides 2009;155:6-10.
PYY

reddot  Peptide tyrosine tyrosine (PYY) is composed of 36 amino-acids, which are cleaved from a 94 amino-acid precursor. It belongs to the family of “tyrosine (Y) peptides”, including neuropeptide Y (NPY), pancreatic polypeptide (PP) and petide Y (found only in fish). Both NPY and PYY have five tyrosines while PP has 4 or 5. It is produced in the ileum (distal part of the small intestine) and in the colon (large intestine) but what precisely causes its secretion remains to be discovered. Levels increase before arrival of the food bolus in the ileum.

reddot  PYY acts as a satiety messenger. PYY readily passes the blood-brain barrier and its receptors (type Y2 and Y4) have been demonstrated in the arcuate nucleus. PPY also act indirectly, through the intermediate of the vagus nerve, with which it interacts at the level of the dorsal vagal complex in the medulla oblongata (area postrema and nucleus of the solitary tract). Like CKK, it has a stimulatory effect, meaning it increases the discharge of neurotransmitters and these somehow have an anorexigenic effect.

reddot  Cases of severe obesity in male Pima Indians (Arizona, New Mexico) are associated with a mutation in PYY, where glutamine-62 is replaced by proline (Q62P). In anorexic humans, levels of PYY are increased fourfold. Agonists of PPY are currently being tested as anti-obesity agents.

  1. Parker SML, Balasubramanian A. Y2 receptors in health and disease. Br J Pharmacology 2008;153:420-431.
The arcuate nucleus target of ghrelin, leptin and insulin

reddot  The arcuate nucleus (in humans also known as the infundibular nucleus) is situated in the mediobasal hypothalamic area of the brain (figure 9 and 10). It constitutes an aggregation of neural cell bodies (or soma) which are visible as dense dots after staining of brain slices with for instance Cresyl violet. These cell bodies are of course connected with other parts of the brain through their dendrites (upstream) and axons (downstream). The cell bodies contain the nucleus of the neuron.

Arcuate nucleus
From arcus (latin), bow or curved, thus translated as “nucleus in the shape of a bow”. In figures often shortened as “Arc”.

Infundibular nucleus
Infundibulum (latin) means funnel. There are quite a few anatomical structures that carry the name infundibulum, such as the entry path of air chambers (alveoli) in the lungs, the outflow portion of the right ventricle of the heart or the mammalian oviduct (fallopian tube) when it approaches the ovary. Here it refers to the funnel shape of the stalk that connects the pituitary with the brain. The arcuate nucleus sits just above that funnel structure and therefore carries the alternative name of “infundibular nucleus”. In figures often shortened as “Inf”.


Figure 9 Anatomical localization of the arcuate nucleus and the surrounding hypothalamic nuclei in a coronal (left) and sagittal (right) section of the human brain.
Abbreviations: Arc, arcuate nucleus, DHA, dorsal hypothalamic area, DMN, dorsomedial nucleus, LHA, lateral hypothalamic area, PeVN, periventricular nucleus), PFA, parafornicular nucleus, PVN, paraventricular nucleus, VMN, ventromedial nucleus, SO, supraoptic nucleus, SC, surprachiasmatic nucleus. Arc and PeVN are drawn transparently in the sagittal section in order to show the underlying nuclei.

Sources:

  1. http://www.netterimages.com
  2. Peyron C et al. figure 2. Nat Med 2000;6:991-997

The arcuate nucleus harbours two types of neurons (figure 10):

  1. neuroendocrine neurons with nerve endings in the median eminence; of these, one population releases the neurohormone dopamine into the hypophysial portal bloodstream leading to inhibition of secretion of prolactin, an anterior-pituitary hormone that stimulates lactation. Dopamine also inhibits the secretion of gonadotropin-releasing hormone produced in the pre-optic area of the hypothalamus. This neurohormone stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thus controlling spermatogenesis (in the male) and ovarian follicular growth, ovulation and maintenance of the corpus luteum (in the female). A second population of neuroendocrine neurons makes growth hormone releasing hormone (GHRH) and this, after release in the hypophysial portal blood, stimulates the secretion of growth hormone.
    (source http://en.citizendium.org/wiki/Arcuate_nucleus)
  2. centrally-projecting neurons; these are of interest to the subject of this webpage. They are located in the most ventromedial part of the nucleus and have projections to many brain areas, including all nuclei in the hypothalamus, of which we mention; the paraventricular nucleus (shortened as PVN, PVH or PN), the lateral hypothalamic area (shortened as LHA or LT) and the perifornical area (shortened as PFA or PF) (see figure 9). These nuclei play a role in the regulation of food intake as we will outline in the next section.


Figure 10 (a) Anatomical position-indicators. For whole organisms: dorsal, ventral, rostral, caudal, dexter and sinister are used. Dexter is on the right when looking from the back. For tissues, organs and cells, a second set of position-indicators is employed: lateral, medial, apical and basal. With respect to the “ventromedial” location of centrally-projecting cells in the arcuate nucleus; this means that you find them “on the belly side of the thalamus towards the middle”, which in this particular case equals ”basomedial” location.

Nomenclature of brain nuclei
For those who are not fully initiated in the field, like us, the naming and abbreviations employed for brain nuclei are hard to grasp. Not only do some use Latin and other English descriptions, the employment of different abbreviations makes it difficult to compare different studies or illustrations. Examples relevant for this webpage; the lateral hypothalamic area is shortened as LHA or LT and the paraventricular nucleus as PVN, PVH or PN. Some figures will shorten the arcuate nucleus as Arc, others as Inf (infundibular nucleus). We learned that the “anterior hypothalamic area” is also referred to as “the anterior nucleus” and that the “pre-optic areas” represent the same anatomical structures as the “medial and lateral pre-optic nuclei”. Or not? Moreover, despite many good brain atlases, navigation in the brain is not particular easy; sagittal or coronal projections give quite different images. And then, for some illustrations mice brains are used and for others humans. Finally, the understanding of neuronal networks is still in its infancy; what is connected to what and what exactly creates the sense of appetite or satiety still requires a lot of fine-tuning. If you find this webpage somewhat confusing with respect to neuronal connections and the neurotransmitters employed, than you now know why.

Centrally projecting neurons of the arcuate nucleus

reddot  Among the centrally-projecting neurons, two different sub-populations are distinguished, each characterized by the neurotransmitters they produce (figure 12):

  1. POMC/CART neurons: involved in the generation of an anorexigenic signal.
    1. POMC stands for pro-opiomelanocortin (P01189 SwissProt), a precursor peptide that is converted by prohormone convertases (in the trans Golgi-network) to yield as many as 10 different active peptide. Amongst these are α- and β-MSH (melanocortins) but also β-endorphorine (hence its name, see figure 11)).
    2. CART, cocaine and amphetamine regulated transcript (Q16568 SwissProt), discovered as a cocaine- and amphetamine-inducible gene. It is a precursor peptide that is converted by prohormone convertase into at least two active peptides (Cart 55-102 and Cart 62-102).


    Figure 11 Multiple mediators derived from the POMC precursor are generated through different cleavages by pro-hormone convertases in the trans-Golgi network (production of secretory vesicles). α-Melanotropin (α-MSH) plays an important role in the generation of the anorexigenic signal (see figure 13).

    Melanocortins
    MSH, melanocyte-stimulating hormone, was discovered as a peptide hormone that induces the production of melanin (pigment) by melanocytes in skin and hair. Later it was shown to exist as a family of hormones including ACTH, α-, β- and γ-MSH and collectively they are referred to as melanocortins. It is the alpha form that plays an important role in pigmentation). Source; wikipedia
  2. AgRP/Npy/GABA neurons: involved in the generation of an orexigenic signal.
    1. AgRP stands for agouti-related protein (O00253 Swiss Prot). It has sequence similarity with Agouti signalling peptide, a hormone that controls coat pigmentation (yellow) in Augoutis (rodents). Aberrant expression of a mutated Agouti protein leads to yellow & obese mice and this pointed to a possible role of Agouti or Agouti-related proteins in the regulation of food intake. Importantly, AgRP acts as an antagonist of the melanocortin receptor-3 and -4 and thus blocks the action of the above mentioned α-MSH in the arcuate nucleus (see figure 13).
    2. Npy, neuropeptide Y (P01303 SwissProt), short peptide that was first isolated from the hypothalamus and resembling PYY produced by the digestive tract (member of the family of tyrosine peptides (see above)).
    3. GABA, gamma-amino-butyric acid, an amino-acid-derived neurotransmitter. It binds to an ion-channel receptor and leads to hyperpolarization of the neuronal membrane (it becomes more difficult to establish an action potential, less firing, less neurotransmitter released from the synapses of the axon)


    Figure 12 Two populations of centrally-projecting neurons in the arcuate nucleus and their projections to other regions in the hypothalamus. POMC/CART are anorexigenic (red represents stop sign) and Npy/AgRP/GABA are orexigenic (green represents go sign).

Insulin, ghrelin and leptin interact with centrally projecting neurons and modulate their activity

reddot  Ghrelin (appetite, orexigenic), insulin and leptin (satiety, anorexigenic) enter the arcuate nucleus. They interact with specific receptors exposed at the surface of the neurons.

  1. Ghrelin binds to and stimulates the Npy/AgRP/GABA neurons. Their neurotransmitters inhibit the activity of the POMC/CART neurons as well as the activity of anorexigenic neurons in the PVN (AgRP is an antagonist of α-MSH). In contrast, Npy/AgRP/GABA neurons stimulate the orexigenic neurons in the LHA/PFA. As a consequence of all this, an orexigenic signal reaches the NTS which in turn brings about a food-seeking behaviour.
  2. Leptin and insulin bind to both the Npy/AgRP/GABA and POMC/CART neurons. They diminish the release of Npy, AgRP and GABA and they augment the release of α-MSH. This leads to activation of anorexigenic neurons in the PVN and inhibition of orexigenic neurons in the LHA/PVA. A predominant anorexigenic signal reaches the NTS, from which a fasting behaviour is orchestrated.

reddot  The above mentioned signals are combined with signals coming from the afferent branches of the vagus nerve (see paragraphs about CCK and PPY). Consult the web page of team 4 for information about the molecular mechanisms that bring about changes in neurotransmitter release.


Figure 13 Regulation of food intake at the level of the arcuate nucleus (ventro-medial hypothalamus).

  1. The orexigenic message of ghrelin enters the brain via the vagus nerve and causes local release of ghrelin from ghrelin-containing neurons. Ghrelin binds to its receptor on Npy/AgRP/GABA neurons, giving rise to an increased production of Npy and AgRP as well as an increased firing rate of these neurons. The consequences are twofold: firstly, inhibition of firing of POMC/CART neurons (through GABA) and secondly stimulation of firing of the orexigenic neurons in the LHA/PFA region (through Npy and AgRP). A predominant orexigenic signal ensues.
  2. Insulin and leptin directly diffuse into the arcuate nucleus and they bind to their receptors on both Npy/AgRP/GABA and POMC/CART neurons. However, they have opposing effects on these neurons. Leptin and insulin promote expression of α-MSH (anorexigenic) but suppress expression of Npy and AgRP (orexigenic). As a consequence a predominant anorexigenic signal ensues.
  3. Messenger abbreviations: Npy, neuropeptide Y, AgRP, agouti-related protein, GABA, gamma-amino butyric acid; α-MSH, alpha-melanocyte stimulating hormone=melanocortin
  4. Receptor abbreviations: GSHR, growth hormone-secretagogue receptor=ghrelin receptor; LepR, leptin receptor; INSR, insulin receptor; Y1R, Npy receptor, MC4R, melanocortin-4 (α-MSH) receptor.

Sources:

  1. Horvath TL. The hardship of obesity: a soft-wired hypothalamus. Nature Neuroscience 2005;8(5): 561-565.
  2. Cone RD. Anatomy and regulation of the central melanocortin system. Nature Neuroscience 2005;8(5): 571-578.
  3. Cowley MA et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003:37:649-661.
  4. Dockray GJ. The versatility of the vagus. Physiology and Behaviour 2009;97:531-536.

 

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Last Updated September 14, 2009 1:56 PM | admin news