Control of appetite Flashcards
What is the distribution of body water?
28L intracellular, 14L ECF, 3L plasma
What is plasma oncotic pressure?
280-290mOsm/L
What are the two main thirst stimuli?
Hypertonic NaCl
Hypertonic glucose
Where are osmoreceptors?
Anterior hypothalamus/preoptic area and subfornical organ, OVLT
What is the OVLT?
Organum vasculosum of the laminae terminalis (OVLT) is a circumventricular organ located along the ventral part of the anterior wall of the third ventricle.
What is the osmotic threshold for stimulation of thirst/drinking?
2-3mOsm
How does the osmotic threshold for vasopressin compare to the osmotic threshold for drinking?
About the same
How can low pressure baroreceptors promote thirst? What pathway?
Low pressure (volume) receptors induce thirst/drinking via vagus (X), nucleus of tractus solitarius, projections to hypothalamus.
Where does water reach to inhibit drinking?
Water in oropharynx / stomach does not stop drinking, while water in duodenum does stop drinking
What osmoreceptors terminate drinking?
Duodenal/portal vein osmoreceptors
Why are pre-absorptive mechanisms important for thirst satiation?
Drinking ends well before much water is absorbed or plasma OP is restored to normal, therefore pre-absorptive mechanisms are important for thirst satiation.
Babinski-Fröhlich-Syndrome
Obesity, hypogonadism, can arise from tumours in hypothalamus (increased appetite and reduced gonadotropin release)
What neurons in the arcuate nucleus regulate appetite?
POMC/CART neurons and NPY/AgRP neurons
What happens to the POMC released from arcuate nucleus neurons? What does it act on?
POMC is converted into αMSH, which is released onto neurons in PVN that express MC4R leading to stimulation
α-MSH is agonist at this receptor
What do POMC/CART neurons express?
Express pro-opiomelanocortin (POMC) and cocaine-and-amphetamine-regulated transcript (CART)
Where else do POMC neurons project to, as well as the PVN?
DMN, LHA and VMN
What does POMC/CART stimulation lead to?
DECREASES food intake
How do POMC neurons affect metabolism?
Increases metabolism, POMC is converted to α-MSH which then stimulates the PVN leading to TRH release
What do NPY/AgRP neurons express?
Express neuropeptide Y (NPY) and agouti-related peptide (AgRP)
What happens to the AgRP released from arcuate nucleus neurons? What does it act on?
AgRP is released onto neurons in PVN that express MC4R leading to their inhibition
AgRP is endogenous antagonist at this receptor
What does NPY activate?
Y receptors
Where else do NPY neurons project to, as well as the PVN?
DMN, VMN, LHA
Where are Y receptors?
Arcuate
What does NPY/AgRP stimulation lead to?
INCREASES food intake
How do NPY/AgRP neurons affect metabolism?
Decrease metabolism, AgRP binds PVN and inhibits neurons, decreases TRH
What is the overall role of the POMC/CART neurons?
POMC/CART neurons inhibit feeding/weight gain
What is the overall role of NPY, AgRP neurons?
Promote feeding and weight gain
What else do NPY/AgRP neurons inhibit?
Inhibit oxytocin-producing neurons in PVN
How do POMC/CART and NPY/AgRP neurons know whether or not food intake should take place?
Hormones: from adipose tissue, from pancreas, from GI tract
Nutrients: glucose, free fatty acids, amino acids
Other neurons
What central neurons can affect appetite?
Brain stem (NTS); analysis centres (amygdala, orbitofrontal cortex), other hypothalamic nuclei, reward pathways (VTA)
What peripheral neurons can affect appetite?
Oropharyngeal, vision, smell, touch
Where is leptin released from?
Adipose
What is the leptin receptor?
ObR
Where is ObR expressed?
Expressed in POMC/CART (activation stimulates) and NPY/AgRP neurons (activation inhibits)
What does leptin binding ObR cause in POMC/CART neurons?
Stimulation - inhibit feeding
What does leptin binding ObR cause in NPY/AgRP neurons?
Inhibition - inhibit feeding
What is the role of leptin?
Leptin decreases food intake and increases metabolism; long-term regulation of food intake and body weight.
Where also express leptin receptors? What is the effect?
VMN (ventromedial nucleus) SF-1 neurons
Stimulation decreases food intake
Selective deletion of ObR in either VMN or arcuate leads to..
Obese mice
Where is insulin released from?
Pancreatic beta cells
What role does insulin have in appetite regulation?
Similar to leptin, reduces food intake and increases metabolism
Where are insulin receptors and what is the effect of binding?
Insulin receptors expressed in POMC/CART and NPY/AgRP neurons in arcuate
Insulin binding stimulates POMC/CART and inhibits NPY/AgRP neurons
Where is pancreatic polypeptide released?
Released from pancreatic PP cells in islets of Langerhans
When is PP released?
In response to meal (in proportion to caloric intake)
Where does PP bind?
Binds to Y4 receptors (GPCR) in brainstem (NTS) and Hypothalamus (Arc, PVN)
What nerve may PP act via?
May act via vagus nerve
What is the effect of PP binding?
Reduces food intake and increases metabolism
What is the only gastric messenger that stimulates food intake and decreases metabolism?
Ghrelin
When does ghrelin concentration rise?
[ghrelin] in plasma rises shortly before meal and falls on feeding
What happens to ghrelin in individuals with prader willi?
Chronically elevated ghrelin
How does ghrelin act and where?
Receptor expressed on NPY/AgRP neurons in arcuate. Stimulates NPY/AgRP and inhibits POMC/CART neurons
How do NPY neurons interact with POMC neurons?
NPY/AgRP neurons make GABAergic contacts with POMC/CART neurons
Where is peptide tyrosine tyrosine (PYY) made?
Produced in ilium and colon in response to food intake (mainly fat, less so carbohydrates or protein)
What are PYY levels in the fasted state?
Low in fasted state and increases following food intake
What is the action of PYY?
Binds to Y receptors (GPCRs) in arcuate nucleus and brainstem
Decreases food intake
What happens to CCK after a meal?
Rises
How can glucose sensing occur due to metabolism?
Metabolism of glucose to produce ATP (i.e. change in intracellular [ATP])
KATP: close in response to ATP binding leads to depolarisation
AMPK: activated when AMP:ATP increases
Allosteric modulation of enzymes by glucose
What cells sense glucose?
Glucose-excited cells (GE) Fire action potentials when glucose rises
Require glucose metabolism for excitation and switching off of KATP channels
Glucose-inhibited cells (GI) Stop firing action potentials when glucose rises
Where are glucose sensing cells?
Arcuate, LHA, VMN and NTS
How does leucine affect metabolism?
Leucine: selectively activates mTOR which decreases food intake and increases metabolism
What amino acids can control food intake?
Essential amino acids: cannot be produced by body and must be taken up by eating. Their presence hence reflects food intake.
What does mTOR activation lead to?
Decreased food intake and increased metabolism
What inhibits mTOR?
AMP kinase
What does AMP kinase promote?
Food intake
What appetite receptors are there in the brainstem - what influence do they have?
Leptin receptors in NTS: decreases food intake
Ghrelin receptors in NTS: promotes food intake
PYY3-36 receptors in NTS: decreases food intake
Glucose sensing neurons in NTS: decreases food intake
Gastric distention (vagus nerve): decreases food intake
Where do brainstem appetite neurons project?
Projects to hypothalamus, particularly ArcN
What is the role of the OFC in appetite?
Combines information on taste, smell and visual inputs; texture representation
Critical for learning which foods to avoid and which to seek out
What is the role of the VTA in food intake?
Reward (dopaminergic neurons, project to nucleus accumbens).
What do leptin receptors in the VTA cause?
Decrease [DA] release and increase DA reuptake
What do ghrelin receptors in the VTA cause?
Increases [DA] release (reward)
What is the role of the NAcc in appetite?
Reward (target of DA neurons from VTA)
Cues previously paired with calories elicit neuronal activation, reflecting reinforcing value of food
Flavours paired with calories are liked more than flavours not paired with calories
What neurons in the lateral hypothalamus help food regulation?
Orexin neurons
MCH neurons (melanin concentrating hormone)
What do orexin neurons do?
Directly excite NPY/AgRP neurons in ArcN (promote lower metabolism and eating)
What do MCH neurons do?
Promote NPY/AgRP release from ArcN (Glucose sensing neurons)
What are orexin and MHC neurons responsible for? What inputs are received?
Receives from ARC, VTA, orbitofrontal cortex and striatum.
Integrative role: integrates homeostatic, satiety and reward related inputs to modulate feeding behaviour
How does the amygdala affect feeding?
Amygdala GABAergic neurons project to LHA glutamatergic neurons
Inhibition of these neurons reduces food intake even in starved animals
What is thought to underpin obesity?
Resistance to insulin and leptin
What can cause leptin resistance?
High fat diet (as opposed to low fat diet with same caloric intake) leads to downregulation of leptin and insulin receptors
Reduced transport of leptin across blood brain barrier
What does ‘lack of leptin’ (due to resistance) stimulate? How are POMC/NPY neurons affected?
Lack of leptin signalling induces starvation responses
Increased NPY and AgRP expression
Changes number and types of synapses on POMC/CART and NPY/AgRP neurons and thereby their activity
More excitation of NPY/AgRP neurons and more inhibition of POMC/CART neurons in ob/ob mice
Significantly more excitatory and significantly fewer inhibitory synapses on NPY/AgRP neurons in ob/ob mice than in wild type mice
Significantly fewer excitatory synapses on POMC/CART neurons in ob/ob mice than in wild type mice
What happens to reproductive hormones and thyroid hormone in low leptin/ leptin resistance?
Reduces production of reproductive hormones and hence fertility to prevent pregnancy
Decreases thyroid hormone production to slow metabolic rate
The action of which of the following in the ventromedial hypothalamus will cause a dose dependent decrease
in food intake and, over a period of weeks, decreased body weight?
Insulin/Leptin
Conversely the administration of which of the following, either centrally or peripherally, will increase food intake and body weight and decrease fat utilization in rodents?
Ghrelin
The orexigenic action of ghrelin is thought to act on the hypothalamic
Arcuate nucleus
Ghrelin activates neurons containing
NPY
Which of the following targets the same hypothalamic site as ghrelin but suppresses food intake?
Leptin
Which of the following brain peptides cause the greatest increase in feeding?
Agouti-related peptide
A gut hormone with tyrosine residues at either end, known as… is able to enter the brain at the ArcN to regulate appetite via non-saturable mechanisms.
PYY
