Control of appetite Flashcards

1
Q

What is the distribution of body water?

A

28L intracellular, 14L ECF, 3L plasma

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2
Q

What is plasma oncotic pressure?

A

280-290mOsm/L

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3
Q

What are the two main thirst stimuli?

A

Hypertonic NaCl

Hypertonic glucose

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4
Q

Where are osmoreceptors?

A

Anterior hypothalamus/preoptic area and subfornical organ, OVLT

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5
Q

What is the OVLT?

A

Organum vasculosum of the laminae terminalis (OVLT) is a circumventricular organ located along the ventral part of the anterior wall of the third ventricle.

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6
Q

What is the osmotic threshold for stimulation of thirst/drinking?

A

2-3mOsm

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7
Q

How does the osmotic threshold for vasopressin compare to the osmotic threshold for drinking?

A

About the same

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8
Q

How can low pressure baroreceptors promote thirst? What pathway?

A

Low pressure (volume) receptors induce thirst/drinking via vagus (X), nucleus of tractus solitarius, projections to hypothalamus.

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9
Q

Where does water reach to inhibit drinking?

A

Water in oropharynx / stomach does not stop drinking, while water in duodenum does stop drinking

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10
Q

What osmoreceptors terminate drinking?

A

Duodenal/portal vein osmoreceptors

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11
Q

Why are pre-absorptive mechanisms important for thirst satiation?

A

Drinking ends well before much water is absorbed or plasma OP is restored to normal, therefore pre-absorptive mechanisms are important for thirst satiation.

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12
Q

Babinski-Fröhlich-Syndrome

A

Obesity, hypogonadism, can arise from tumours in hypothalamus (increased appetite and reduced gonadotropin release)

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13
Q

What neurons in the arcuate nucleus regulate appetite?

A

POMC/CART neurons and NPY/AgRP neurons

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14
Q

What happens to the POMC released from arcuate nucleus neurons? What does it act on?

A

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

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15
Q

What do POMC/CART neurons express?

A

Express pro-opiomelanocortin (POMC) and cocaine-and-amphetamine-regulated transcript (CART)

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16
Q

Where else do POMC neurons project to, as well as the PVN?

A

DMN, LHA and VMN

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17
Q

What does POMC/CART stimulation lead to?

A

DECREASES food intake

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18
Q

How do POMC neurons affect metabolism?

A

Increases metabolism, POMC is converted to α-MSH which then stimulates the PVN leading to TRH release

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19
Q

What do NPY/AgRP neurons express?

A

Express neuropeptide Y (NPY) and agouti-related peptide (AgRP)

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20
Q

What happens to the AgRP released from arcuate nucleus neurons? What does it act on?

A

AgRP is released onto neurons in PVN that express MC4R leading to their inhibition

AgRP is endogenous antagonist at this receptor

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21
Q

What does NPY activate?

A

Y receptors

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22
Q

Where else do NPY neurons project to, as well as the PVN?

A

DMN, VMN, LHA

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23
Q

Where are Y receptors?

A

Arcuate

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24
Q

What does NPY/AgRP stimulation lead to?

A

INCREASES food intake

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25
Q

How do NPY/AgRP neurons affect metabolism?

A

Decrease metabolism, AgRP binds PVN and inhibits neurons, decreases TRH

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26
Q

What is the overall role of the POMC/CART neurons?

A

POMC/CART neurons inhibit feeding/weight gain

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27
Q

What is the overall role of NPY, AgRP neurons?

A

Promote feeding and weight gain

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28
Q

What else do NPY/AgRP neurons inhibit?

A

Inhibit oxytocin-producing neurons in PVN

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29
Q

How do POMC/CART and NPY/AgRP neurons know whether or not food intake should take place?

A

Hormones: from adipose tissue, from pancreas, from GI tract

Nutrients: glucose, free fatty acids, amino acids

Other neurons

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30
Q

What central neurons can affect appetite?

A

Brain stem (NTS); analysis centres (amygdala, orbitofrontal cortex), other hypothalamic nuclei, reward pathways (VTA)

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31
Q

What peripheral neurons can affect appetite?

A

Oropharyngeal, vision, smell, touch

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32
Q

Where is leptin released from?

A

Adipose

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33
Q

What is the leptin receptor?

A

ObR

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34
Q

Where is ObR expressed?

A

Expressed in POMC/CART (activation stimulates) and NPY/AgRP neurons (activation inhibits)

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35
Q

What does leptin binding ObR cause in POMC/CART neurons?

A

Stimulation - inhibit feeding

36
Q

What does leptin binding ObR cause in NPY/AgRP neurons?

A

Inhibition - inhibit feeding

37
Q

What is the role of leptin?

A

Leptin decreases food intake and increases metabolism; long-term regulation of food intake and body weight.

38
Q

Where also express leptin receptors? What is the effect?

A

VMN (ventromedial nucleus) SF-1 neurons

Stimulation decreases food intake

39
Q

Selective deletion of ObR in either VMN or arcuate leads to..

A

Obese mice

40
Q

Where is insulin released from?

A

Pancreatic beta cells

41
Q

What role does insulin have in appetite regulation?

A

Similar to leptin, reduces food intake and increases metabolism

42
Q

Where are insulin receptors and what is the effect of binding?

A

Insulin receptors expressed in POMC/CART and NPY/AgRP neurons in arcuate

Insulin binding stimulates POMC/CART and inhibits NPY/AgRP neurons

43
Q

Where is pancreatic polypeptide released?

A

Released from pancreatic PP cells in islets of Langerhans

44
Q

When is PP released?

A

In response to meal (in proportion to caloric intake)

45
Q

Where does PP bind?

A

Binds to Y4 receptors (GPCR) in brainstem (NTS) and Hypothalamus (Arc, PVN)

46
Q

What nerve may PP act via?

A

May act via vagus nerve

47
Q

What is the effect of PP binding?

A

Reduces food intake and increases metabolism

48
Q

What is the only gastric messenger that stimulates food intake and decreases metabolism?

A

Ghrelin

49
Q

When does ghrelin concentration rise?

A

[ghrelin] in plasma rises shortly before meal and falls on feeding

50
Q

What happens to ghrelin in individuals with prader willi?

A

Chronically elevated ghrelin

51
Q

How does ghrelin act and where?

A

Receptor expressed on NPY/AgRP neurons in arcuate. Stimulates NPY/AgRP and inhibits POMC/CART neurons

52
Q

How do NPY neurons interact with POMC neurons?

A

NPY/AgRP neurons make GABAergic contacts with POMC/CART neurons

53
Q

Where is peptide tyrosine tyrosine (PYY) made?

A

Produced in ilium and colon in response to food intake (mainly fat, less so carbohydrates or protein)

54
Q

What are PYY levels in the fasted state?

A

Low in fasted state and increases following food intake

55
Q

What is the action of PYY?

A

Binds to Y receptors (GPCRs) in arcuate nucleus and brainstem

Decreases food intake

56
Q

What happens to CCK after a meal?

A

Rises

57
Q

How can glucose sensing occur due to metabolism?

A

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

58
Q

What cells sense glucose?

A

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

59
Q

Where are glucose sensing cells?

A

Arcuate, LHA, VMN and NTS

60
Q

How does leucine affect metabolism?

A

Leucine: selectively activates mTOR which decreases food intake and increases metabolism

61
Q

What amino acids can control food intake?

A

Essential amino acids: cannot be produced by body and must be taken up by eating. Their presence hence reflects food intake.

62
Q

What does mTOR activation lead to?

A

Decreased food intake and increased metabolism

63
Q

What inhibits mTOR?

A

AMP kinase

64
Q

What does AMP kinase promote?

A

Food intake

65
Q

What appetite receptors are there in the brainstem - what influence do they have?

A

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

66
Q

Where do brainstem appetite neurons project?

A

Projects to hypothalamus, particularly ArcN

67
Q

What is the role of the OFC in appetite?

A

Combines information on taste, smell and visual inputs; texture representation

Critical for learning which foods to avoid and which to seek out

68
Q

What is the role of the VTA in food intake?

A

Reward (dopaminergic neurons, project to nucleus accumbens).

69
Q

What do leptin receptors in the VTA cause?

A

Decrease [DA] release and increase DA reuptake

70
Q

What do ghrelin receptors in the VTA cause?

A

Increases [DA] release (reward)

71
Q

What is the role of the NAcc in appetite?

A

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

72
Q

What neurons in the lateral hypothalamus help food regulation?

A

Orexin neurons

MCH neurons (melanin concentrating hormone)

73
Q

What do orexin neurons do?

A

Directly excite NPY/AgRP neurons in ArcN (promote lower metabolism and eating)

74
Q

What do MCH neurons do?

A

Promote NPY/AgRP release from ArcN (Glucose sensing neurons)

75
Q

What are orexin and MHC neurons responsible for? What inputs are received?

A

Receives from ARC, VTA, orbitofrontal cortex and striatum.

Integrative role: integrates homeostatic, satiety and reward related inputs to modulate feeding behaviour

76
Q

How does the amygdala affect feeding?

A

Amygdala GABAergic neurons project to LHA glutamatergic neurons

Inhibition of these neurons reduces food intake even in starved animals

77
Q

What is thought to underpin obesity?

A

Resistance to insulin and leptin

78
Q

What can cause leptin resistance?

A

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

79
Q

What does ‘lack of leptin’ (due to resistance) stimulate? How are POMC/NPY neurons affected?

A

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

80
Q

What happens to reproductive hormones and thyroid hormone in low leptin/ leptin resistance?

A

Reduces production of reproductive hormones and hence fertility to prevent pregnancy

Decreases thyroid hormone production to slow metabolic rate

81
Q

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?

A

Insulin/Leptin

82
Q

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?

A

Ghrelin

83
Q

The orexigenic action of ghrelin is thought to act on the hypothalamic

A

Arcuate nucleus

84
Q

Ghrelin activates neurons containing

A

NPY

85
Q

Which of the following targets the same hypothalamic site as ghrelin but suppresses food intake?

A

Leptin

86
Q

Which of the following brain peptides cause the greatest increase in feeding?

A

Agouti-related peptide

87
Q

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.

A

PYY