1B appetite Flashcards
(72 cards)
1
Q
What are the 3 main triggers through which the body controls thirst?
A
- Body fluid osmolality
- Blood volume is reduced
- Blood pressure is reduced
2
Q
Which of blood osmolality, volume and pressure is the most potent stimulus?
A
- Plasma osmolality- a change of 2-3% induces a strong desire to drink
- Decrease of 10-15% in blood volume or arterial pressure is required to have the same effect
3
Q
How does the body regulate osmolality?
A
Using ADH (vasopressin)
- It acts on kidneys in the collecting duct through the aquaporin 2 channel to regulate the volume and osmolality of urine
- When plasma ADH is low a large volume of urine is excreted → called water diuresis
- When plasma ADH is high a small volume of urine is excreted → called anti diuresis
4
Q
Where is ADH stored?
A
In the posterior pituitary
5
Q
How does the body detect changes in osmolality?
A
- Through osmoreceptors, which are sensory receptors
- Changes in osmolality leads to secretion or reduction of ADH
6
Q
Where are osmoreceptors found?
A
Hypothalamus:
- Organum vasculosum of the lamina terminalis (OVLT)
- Subfornical organ (SFO)
7
Q
How do osmoreceptors respond when the plasma is hypertonic?
A
1) Under normal conditions, a set proportion of cation channels in osmoreceptor cells are active
2) Under hypertonic (more concentrated plasma) stimulation, the cell shrinks
3) This increases proportion of active cation channels- results in increasing positive charge influx which depolarises membrane
4) This sends signals to the ADH producing cells to increase ADH
5) Leads to fluid retention and invokes drinking
8
Q
How do the osmoreceptors respond when plasma is hypotonic?
A
1) Under normal conditions, a set proportion of cation channels in osmoreceptor cells are active
2) Under hypotonic (less concentrated plasma) stimulation, the cell expands
3) This inhibits cation channels. The loss of cation influx causes a decreases positive charge influx which hyperpolarises membrane.
4) This inhibits neuronal firing.
9
Q
Define thirst
A
The desire to drink
10
Q
What’s the deal with water absorption and plasma osmolality correction?
A
- There is a delay between water absorption in GI tract and plasma osmolality correction as water is absorbed and circulates around body
- So, overdrinking can be an issue, which the kidneys could potentially deal with by expelling more water, but this wastes energy and can interfere with nutrient absorption which is sodium driven
11
Q
How does the body deal with complications that could cause overdrinking?
A
- Thirst is decreased by drinking even before sufficient water has been absorbed by GI tract to correct plasma osmolality
- There are receptors in mouth, pharynx, oesophagus that are involved to relieve thirst
- However, this relief of thirst via these receptors is short lived
12
Q
When is thirst completely satisfied?
A
Once plasma osmolality is decreased or blood volume or arterial pressure are corrected
13
Q
Describe the RAAS
A
This is the less effective way of controlling thirst
- When bp drops, JG apparatus secretes renin
- Renin is aka angiotensinogenase, an enzyme, and cleaves angiotensinogen secreted by liver to activate it to become angiotensin I
- Angiotensin I then converted into angiotensin II by ACE which happens in lungs
14
Q
Effects of angiotensin II?
A
- Induces thirst
- Also binds onto receptors on intraglomerular messenger cells, which causes cells to contract along with blood vessels around them → leads to aldosterone release in zona glomerulosa of adrenal cortex
- Aldosterone retains water through Na+Cl- absorption and K+ secretion
- Also causes ADH secretion
- Activates sympathetic NS causing vasoconstriction
15
Q
What 2 important types of drugs are important in this system?
A
- Direct renin inhibitors
- ACE inhibitors
- Both used to treat bp
16
Q
What does the body do if fat mass is reduced?
A
Try to gain weight by:
- Sympathetic NS energy activity decreases
- Energy expenditure decreases
- Hunger/food intake increases
- Thyroid activity decreased
17
Q
What does the body do if fat mass is increased?
A
Try to decrease weight by:
- Increasing sympathetic nervous system activity
- Increasing energy expenditure
- Decreasing hunger/food intake
18
Q
What body system defends against rapid expansion of fat mass?
A
Yet to be discovered
19
Q
Where does appetite regulation occur?
A
Hypothalamus
20
Q
What peripheral stimuli are there that are involved in appetite regulation?
A
- Ghrelin, PYY and other gut hormones- communicate through vagus nerve to brainstem which communicates with hypothalamus which then communicated with higher CNS regions like amygdala
- Neural input from the periphery and other brain regions
- Leptin (via leptin control system)
21
Q
How does the hypothalamus sensitise a response?
A
By increasing or decreasing energy expenditure and food intake
22
Q
What is the arcuate nucleus responsible for?
A
- It’s an aggregation of neurones in the medial basal part of the hypothalamus and is adjacent to the 3rd ventricle
- It has:
- orexigenic (appetite stimulating/increasing) neurones
- anorectic (appetite suppressive) neurones
23
Q
When does the arcuate nucleus decrease food intake?
A
When its pro-opiomelanocortin (POMC) neurones activate
24
Q
What does the paraventricular nucleus do?
A
- Lays adjacent to 3rd ventricle
- Contains neurones that project to posterior pituitary and secrete oxytocin and ADH, to regulate osmoregulation, appetite and stress reaction of the body
25
What does the lateral hypothalamus do?
Produces only orexigenic peptides
26
What does the ventromedial hypothalamus do?
- Associated with satiety
- Lesions in this region in rats leads to severe obesity
27
What other hypothalamic factors are implicated in appetite regulation?
- Endocannabinoids
- AMP (activated protein kinase)
- Protein tyrosine phosphatase
28
What does the arcuate nucleus do?
- Brain area involved in regulation of food intake
- Integrates **peripheral** and **central** feeding signals
29
What is its BBB like in arcuate nucleus and why?
Incomplete BBB to allow access to peripheral hormones
30
What two neuronal populations does the arcuate nucleus have?
- Stimulatory neurones
- Inhibitory neurones
31
What peptides do stimulatory neurones produce?
- neuropeptide Y (NPY)
- Agouti-related peptide (Agrp)
32
What do NPY and Agrp do?
Stimulate food intake by:
- Increasing neuropeptide Y signalling
- Reducing melanocortin signalling via release of Agrp (an endogenous melanocortin receptor antagonist)
33
What peptide do inhibitory neurones produce?
POMC
34
What do circulating factors do when they reach the hypothalamus in the blood?
- Cross incomplete BBB and penetrate arcuate nucleus
- Either POMC neurones or NPY/Agrp neurones are activated which both go to the paraventricular nucleus
35
How does the melanocortin system work?
- Melanocortin 4 receptors are expressed on paraventricular nucleus
- Agrp neurones release Agrp which act on MC4R as antagonists
- POMC neurones produce melanocortins, classic example is alpha-MSH, which act on MC4R as agonists → leads to decrease in appetite and weight along with food intake
36
What do NPY or Agrp mutations do to appetite?
No NPY or Agrp mutations are associated with appetite in humans
37
What can POMC deficiency cause?
Morbid obesity
38
What can MC4R mutations cause?
Morbid obesity
39
What are looking into these mutations useful for?
Not to explain prevalence of obesity, but useful to explain signalling
40
What signals from other brain regions are involved in controlling appetite?
- Higher centres e.g. amygdala- responsible for emotion and memory and controlling reward related motivation pathways which has strong effect on appetite
- Lateral hypothalamus and ventromedial hypothalamus
- Vagus communication from digestive tract to brain stem then hypothalamus then amygdala (these 3 centres work together to regulate appetite)
41
What is the adipostat mechanism?
The body’s thermostat i.e. control of energy expenditure through thermoregulation (controlling body temp) which keeps individual’s fat mass within narrow range despite changes to diet or daily activity
42
How does adipose tissue interact with hypothalamus for it to regulate food intake?
- **Circulating hormones are produced** by adipose tissue- the more adipose tissue, the more hormones being produced
- Hypothalamus senses **conc of hormones** then alters neuropeptides to increase or decrease food intake
43
Describe the ob/ob mouse experiment
- A mouse with a mutation that means it can’t produce the hormone leptin
- This leads to severe obesity in the mouse as it eats excessively
- It develops high blood sugar, pancreatic islet cell enlargement and increased insulin levels
44
What is leptin?
- A hormone made by white adipose tissue and enterocytes in small intestines
- Circulates in plasma
- Regulates appetite (intake) and thermogenesis (expenditure)
45
Where does leptin act?
Acts upon cell receptors in the arcuate and ventromedial nuclei
46
What is congenital leptin deficiency?
- Incredibly rare genetic condition that causes severe obesity very early in life as they have low levels of serum leptin
- Those with it are born with a normal weight but are always hungry and constantly eat so gain weight quickly
- Only few people known to have defect
47
What are leptin levels like in obese patients?
- Serum leptin is significantly higher in obese subjects than normal weight people
- Serum leptin is correlated with percentage of body fat of subjects
48
What does this suggest?
Most obese people are resistant to endogenous leptin production
49
Describe the overall systemic effects of leptin
- It’s low when there’s low body fat
- It’s high when there’s high body fat
- Replacement of leptin in ob/ob mouse decreases weight
- It’s a hormone that decreases food intake and increases thermogenesis
50
What are the 3 main mechanisms through which the physiological effect of leptin may not work?
- **Absence**: There is insufficient production of leptin
- **Regulatory defect**: There is a defect in the regulatory signalling and reduced leptin levels despite high adipose tissue mass
- **Resistance**: There is a decreased sensitivity to leptin (similar to insulin resistance in T2DM)- this results in inability to detect satiety despite high energy stores and leptin levels
51
How do leptin levels relate to fat mass (and what does this have to do with leptin resistance)?
- Leptin circulates in plasma in concs proportional to fat mass → fat people have high leptin
- This proves leptin resistance is a thing
52
What does leptin resistance cause?
Obesity since the hormone is present but doesn’t signal effectively
53
How effective is leptin as a weight control drug?
It's not effective
54
Why do we feel less hungry after a meal?
- Not due to bulk in the stomach
- It is due to nutrients in the circulation to an extent
- The main reason is hormone signals from gut
55
What secretes GI hormones?
Enteroendocrine cells in stomach, pancreas and small bowel
56
What do GI hormones control?
Various functions of digestive organs e.g. motility, appetite, satiety, salivation etc
57
What are the 2 important hormones appetite regulation-wise (and what do they do)?
- Ghrelin → stimulates appetite, increases gastric emptying
- Peptide YY (PYY) → inhibits food intake
58
When are blood ghrelin levels highest and why?
Before meals to help prep for food intake by increasing gastric motility and acid secretion
Returns to lower levels after meal times
59
What is ghrelin's name based on?
On its role as a growth hormone-releasing peptide (GHRE)
60
What is ghrelin also known as?
Hunger hormone because it increases food intake
61
How does ghrelin work in the hypothalamus?
Directly modulates neurones in the arcuate nucleus
- Stimulates NPY/Agrp neurones
- Inhibits POMC neurones
62
What are the roles of ghrelin?
- Increases appetite
- Regulation of reward, taste sensation, memory and circadian rhythm
63
Describe what's happening in this graph
- Plasma ghrelin levels increased nearly 2x immediately before each meal time
- Fell to a trough around 1 after meal time
- Intermeal ghrelin levels have a diurnal rhythm- rise throughout day to zenith at 1am then falling overnight to a nadir at 9am
64
What else does ghrelin plasma levels correlate positively with?
Age
65
What is the effect of ghrelin on food intake levels?
More ghrelin means more cumulative food intake which was associated with excess weight gain and adiposity in mice.
In humans, energy intake was a lot higher when ghrelin was given intravenously to subjects vs saline (they ate more from a buffet they were given)
66
What is peptide tyrosine tyrosine (PYY)?
Short peptide (36 amino acids) released in terminal ileum and colon in response to feeding
67
What does PYY do?
Reduces appetite- can be digested or injected IV
68
How does PYY act in hypothalamus?
- Inhibits NPY release
- Stimulates POMC neurones
69
What causes PYY release?
Food arriving in terminal ileum and colon
70
What is the PYY effect on feeding in mice?
It decreases food intake
The degree of PYY release is proportional (postprandially) to the calorie intake
71
What is the PYY effect on feeding in humans?
- PYY infusions resulted in dose-dependent reduction in food and calorie intake with maximal inhibition of 35% compared to saline administration
- Fluid ingestion also reduced
72
What comorbidities is obesity associated with?
- Depression
- Stroke
- Myocardial infarction
- Hypertension
- Diabetes
- Peripheral vascular disease
- Gout
- Osteoarthritis
- Bowel cancer and maybe breast cancer
- Sleep apnoea
