Appetite

Question 1

Control of thirst caused by

Answer 1

Body Fluid Osmolality (increasing increases thirst) - change of 2/3% to induce thirst
-Blood volume (reduction increases thirst) - change of 10-15% to induce thirst
-Blood pressure (reduction increases thirst) - change of 10-15% to induce thirst

Question 2

Regulation of osmolality

Answer 2

ADH- acts on kidneys
Low ADH= large volume of urine, water diuresis
High ADH= low diuresis

Released and stored from posterior pituitary

Question 3

Osmoreceptors

Answer 3

Measure osmolality

Found in hypothalamus:

1. Organum Vasculosum of the Lamina Terminalis (OVLT)
2. Subfornical Organ (SFO)

Cells shrink when plasma is more concentrated
Proportion of action channel increase and membrane depolarizes
Sends signals to ADH producing cells to increase ADH
Fluid retention involves drinking

Question 4

Sensation of thirst

Answer 4

• Thirst is decreased by drinking even before there is sufficient water absorption in the GI tract to correct the plasma osmolality
• This is because there are receptors in the mouth, pharynx and oesophagus
• Thirst is only fully satisfied once plasma osmolality has decreased or blood volume / pressure are corrected

Question 5

Renin-angiotensin-aldosterone system

Answer 5

• Blood pressure falling leads to excretion of renin from juxtaglomerular cells of renal afferent arteriole
• Angiotensinogen converted to angiotensin I by renin
• ACE from lungs cleaves angiotensin I into angiotensin II
• Angiotensin II increases ADH secretion, increases thirst
• Angiotensin II also causes influx of potassium and efflux of sodium from the zona glomerulosa of the adrenal cortex, resulting in aldosterone release, which then promotes systemic H2O retention due to Na+ and Cl- absorption, alongside K+ excretion
  Angiotensin II also causes vasoconstriction and increases sympathetic activity

Question 6

Homeostasis

Answer 6

1. Neuman 1902 - noticed maintaining body weight didn’t need active input
2. Passmore 1971 - noticed most adults maintain stable weight
3. Reduction in fat mass increases food intake and reduces energy expenditure
4. Adipose tissue expansion reduces food intake and increases energy expenditure

System underpinning rapid weight loss is well understood, but there is no knowledge of what prevents rapid weight gain

##

Question 7

Melanocortin system

Answer 7

POMC > a-MSH stimulates MC4R in the paraventricular Nucleus

POMC and MC4R mutations associated with human obesity

Amygdala, latera hypothalamus, vagus nerve all transmit signals about hunger

Question 8

What does the body do if fat mass reduces

Answer 8

Try to gain weight by:

• Sympathetic NS energy activity decreases
• Energy expenditure decreases
• Hunger/food intake increases
• Thyroid activity decreased

Question 9

• What does the body do if fat mass is increased?

Answer 9

• Increasing sympathetic nervous system activity
• Increasing energy expenditure
• Decreasing hunger/food intake

Question 10

What body system defends against rapid expansion of fat mass?

Answer 10

Not discovered yet

Question 11

Where does appetite regulation occur

Answer 11

Hypothalamus

Question 12

What peripheral stimuli are there that are involved in appetite regulation?

Answer 12

• 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)

Question 13

How does the hypothalamus sensitise a response

Answer 13

By increasing or decreasing energy expenditure and food intake

Question 14

What is the arcuate nucleus responsible for?

Answer 14

• 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

Stimulatory-NPY/AGRP
inhibitory-POMC

Question 15

When does the arcuate nucleus decrease food intake?

Answer 15

When its pro-opiomelanocortin (POMC) neurones activate

Question 16

What does the paraventricular nucleus do?

Answer 16

• 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

Question 17

What does the lateral hypothalamus do?

Answer 17

Produces only orexigenic peptides
(Feeding centre)

Question 18

What does the ventromedial hypothalamus do?

Answer 18

• Associated with satiety
• Lesions in this region in rats leads to severe obesity
  Is an appetite suppressant

Question 19

Arcutae nucleus

Answer 19

• Brain area involved in regulation of food intake
• Integrates peripheral and central feeding signals
  Has an incomplete BBB to allow access to peripheral hormones

Question 20

What 2 neuronal populations does the arcuate nucleus have

Answer 20

Stimulatory and inhibitory

Question 21

Stimulatory neurones in arcuate nucleus

Answer 21

• neuropeptide Y (NPY)
• Agouti-related peptide (Agrp)
• Increasing neuropeptide Y signalling
• Reducing melanocortin signalling via release of Agrp (an endogenous melanocortin receptor antagonist)

Question 22

Inhibitory neurones in arcuate nucleus make

Answer 22

POMC

Question 23

What receptors for other hormones does arcuate nucleus have

Answer 23

For leptin and insulin, and are activated by a decrease or increase of leptin or insulin signalling

• what leads to increased food intaks
  
  • Fasting
  • Uncontrolled diabetes
  • General leptin deficiency

Question 24

What do circulating factors do when they reach the hypothalamus in the blood?

Answer 24

• Cross incomplete BBB and penetrate arcuate nucleus
• Either POMC neurones or NPY/Agrp neurones are activated which both go to the paraventricular nucleus

• • Fertility regulation
  • Cardiovascular regulation

Question 25

Besides feeding, what other 2 important things is the arcuate nucleus involved in?

Answer 25

- Fertility regulation - Cardiovascular regulation

Question 26

How does the melanocortin system work?

Answer 26

- 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

Question 27

What do NPY or Agrp mutations do to appetite?

Answer 27

No NPY or Agrp mutations are associated with appetite in humans

Question 28

What can POMC deficiency cause?

Answer 28

Morbid obesity

Question 29

What can MC4R mutations cause?

Answer 29

Morbid obesity

Question 30

What signals from other brain regions are involved in controlling appetite?

Answer 30

- 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)

Question 31

What is the adipostat mechanism?

Answer 31

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

Question 32

How does adipose tissue interact with hypothalamus for it to regulate food intake?

Answer 32

- 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

Question 33

Describe the ob/ob mouse experiment

Answer 33

- 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

Question 34

What is leptin?

Answer 34

- A hormone made by white adipose tissue and gastric mucosaintestines - Circulates in plasma - decreases appetite (intake) and increasesthermogenesis (expenditure Increases acutely post prandially Acts in cells in **arcuate and ventromedial nuclei**

Question 35

What is congenital leptin deficiency?

Answer 35

- 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

Question 36

What are leptin levels like in obese patients?

Answer 36

- Serum leptin is significantly higher in obese subjects than normal weight people - Serum leptin is correlated with percentage of body fat of subjects Obese people beck,e resistant to leptin production

Question 37

Describe the overall systemic effects of leptin

Answer 37

- 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

Question 38

What are the 3 main mechanisms through which the physiological effect of leptin may not work?

Answer 38

- There is insufficient production of leptin - There is a defect in the regulatory signalling and reduced leptin levels despite high adipose tissue mass - 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

Question 39

How effective is leptin as a weight control drug?

Answer 39

Not effective

Question 40

What secreted GI hormones

Answer 40

Enteroendocrine cells which control motility appetite salivation etc

Question 41

What are the 2 important hormones appetite regulation-wise (and what do they do)?

Answer 41

- Ghrelin → stimulates appetite, increases gastric emptying - Peptide YY (PYY) and GLP-1→ inhibits food intake

Question 42

When are blood ghrelin levels highest and why?

Answer 42

Before meals to help prep for food intake by increasing gastric motility and acid secretion Returns to lower levels after meal times

Question 43

What is ghrelin known as

Answer 43

Hunger hormone as infeases food intake Its name derived from role of growth hormone releasing peptide

Question 44

How does ghrelin work in arcuate nucleus

Answer 44

Directly modulates neurones in the arcuate nucleus - Stimulates NPY/Agrp neurones - Inhibits POMC neurones Thus increases appetite and regulates reward taste sensation memory and circadian rhythm

Question 45

Ghrelin throughout day

Answer 45

- 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 Also correlates with age

Question 46

PYY

Answer 46

Short peptide (36 amino acids) released in terminal ileum and colon in response to feeding Reduces appetite can be digested or injected iv

Question 47

How does PYY act on hypothalamus

Answer 47

- Inhibits NPY release - Stimulates POMC neurones Release caused by food arrival in terminal ileum and colon

Question 48

What food types increase PYY release?

Answer 48

- Dietary fibres - wholegrains - enzymatic breakdown of crude fish proteins

Question 49

Effect of PYY on mice and humans

Answer 49

It decreases food intake The degree of PYY release is proportional (postprandially) to the calorie intake - How about 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

Question 50

What comorbidities is obesity associated with

Answer 50

- Depression- stat 1/3 of people with BMI >35 have depression - Stroke - Myocardial infarction - Hypertension - Diabetes - Peripheral vascular disease - Gout - Osteoarthritis- how? Obese subjects’ joints need to carry more weight - Bowel cancer and maybe breast cancer - Sleep apnoea- how? - Swollen airways lead to sleep apnoea - This causes tiredness which affects reward mechanism and increases people’s food intake

Question 51

GLP 1

Answer 51

short peptide released in gut in relosnse to feeding (30 amino acids) Reduces appetite can be Incretin increases insulin release in response to glucose

Question 52

The genetics

Answer 52

Mknogenic obesity rare Genetic factors explain 40% of variance in obesity Around 250 genes associated with obesity Thrifty genes protect us from starvation allowing us to store energy

Question 53

BMI categories

Answer 53

underweight <18.5 healthy is 18.5-25 overweight is 25-30 obesity class-30-45 class 2-35-40 class 3-40+