Obesity and endocrine control of food intake

Question 1

What is the energy expenditure balance like?

Answer 1

• Input = food intake
• Output = BMR + exercise

Question 2

1) List 4 inputs that the hypothalamus has from other places that impact the appetite and briefly detail how they impact it - note 2 of these biochemical inputs have 2 opposing effects so there’ll be 6 listed inputs but there’ll be two repeats

Answer 2

NOTE: remember the melanocortin pathway is via the MC4R neurones which are modulated by the NPY / AgRP and POMC neurones in the arcuate nucleus and remember MC4R lowers appetite and that NPY / AgRP inhibits MC4R and POMC stimulates MC4R

1. Ghrelin from stomach stimulates NPY / AgRP at the arcuate nucleus to increase appetite and also inhibits POMC to increase appetite
2. PPY from colon inhibits NPY / AgRP at the arcuate nucleus to lower appetite and also activates POMC to lower appetite
3. Leptin from stomach inhibits NPY / AgRP at the arcuate nucleus to lower appetite
4. Leptin from stomach activates POMC to increase appetite
5. Insulin from pancreas stimulates the conversion of POMC into ACTH and α-MSH at the arcuate nucleus to increase appetite
6. Insulin from pancreas also inhibits the NPY / AgRP at the arcuate nucleus to lower appetite

Question 3

Label the diagram

Answer 3

Question 4

Where is the arcuate nucleus located anatomically and what is the significance of its anatomical location functionally?

Answer 4

• Located above the median eminence so its not completely isolated from blood circulation by the BBB so can receive peripheral hormone signalling

Question 5

What are the 2 neuronal populations in the arcuate nucleus and what are their functions?

Answer 5

1. NPY / AgPR - inhibitory to the MC4R (therefore increase appetite)
2. POMC - stimulatory to the MC4R (therefore decrease appetite)

Question 6

Outline the mechanisms of functionality of the melanocortin system

Answer 6

• MC4R inhibits appetite
• NPY / AgPR - inhibitory to the MC4R (therefore increase appetite)
• POMC - stimulatory to the MC4R (therefore decrease appetite)

Question 7

What deficiencies or mutations affecting the direct melanocortin pathway are linked adversely to appetite and therefore obesity and what other clinical signs are associated with one of them?

Answer 7

• No known NYP or AgRP mutations known to do with appetite
• M4CR mutation causes increase in appetite
• POMC deficiency - so signs associated with decreased cleavage products - causes increased appetite thus obesity due to low α-MSH, paleness due to low α-MSH, ginger due to low α-MSH, cortisol deficiency too due to lack of ACTH cleavage product

Question 8

1) What mutation that relates to leptin results in obesity and outline how?
2) What clinical signs are associated with this defect?

Answer 8

1)

• Recessive mutation in the ob/ob gene
• So dysfunctional leptin protein - essentially leptin deficient
• So there is little / no leptin inhibition of the NPY / AgPR neurones or stimulation of POMC in the arcuate nucleus of the hypothalamus so there is increased appetite

2)

• Obese
• Diabetic
• Infertile - reproductive axis shuts down because body thinks you’re starving
• Stunted linear growth
• Low body temperature
• Impaired immune function - because immune function requires lots of energy and if the body thinks you’re starving it shuts down the immune system

Question 9

Where is leptin secreted from and why might this be significant?

Answer 9

• Leptin is secreted from adipose tissue
• So thin people do not secrete much leptin so they should have a higher appetite theoretically
• So obese people secrete loads of leptin so theoretically they should have a lower appetite, but in reality this does not really affect their appetites, due probably to leptin resistance

Question 10

What effects will happen if you administrate leptin centrally or peripherally (except in those resistant - which is a lot of obese people)?

Answer 10

• Decrease appetite
• Increase thermogenesis - get hotter

Question 11

Leptin circulates in plasma in concentrations proportional to …..

Answer 11

Leptin circulates in plasma in concentrations proportional to fat mass

Question 12

What effects will the absence of leptin have?

Answer 12

• Hyperphagia
• Lowered expenditure
• Sterility

Question 13

1) How is the administration of leptin used therapeutically - 3 ways?
2) Why can’t you just administer leptin in obese people?

Answer 13

1)

• Used in those who are actually leptin deficient
• Restores LH pulsatility in children who are leptin deficient
• Restores LH pulsatility in women with amenorrhoea due to low body fat and stress

2)

• Because people aren’t usually leptin deficient, just resistant to leptin. So even if you administrate leptin it will have little effect due to resistance

Question 14

Insulin circulates at levels proportional to ….. …..

Answer 14

Insulin circulates at levels proportional to body fat

Question 15

What effect will central administration of insulin have?

Answer 15

• Lowers food intake

Question 16

Describe how PYY is secreted and how it has its physiological function

Answer 16

• Secreted from the small intestine in response to a meal
• Its secretion is proportional to caloric intake
• In order to become activated, PYY (which is a 36 A.A. protein) has 2 A.As cleaved to form PPY_3-36
• PYY inhibits NPY/AgRP and stimulates POMC to inhibit MC4R overall, thereby decreasing appetite

Question 17

Where is GLP-1 excreted from?

Answer 17

L-cells of the small intestine

Question 18

How is GLP-1 formed and secreted and where does this processing occur?

Answer 18

• Coded for by the glucagon gene
• Excised from the pre-proglucagon molecule initially produced within the L-cells of the small intestine
• Secreted by intestinal L-cells

Question 19

What is GLP-1 released in response to and what is its physiological function?

Answer 19

• Secreted post-prandially (after meals)
• Incretin effect on insulin release in response to glucose - i.e. potentiates the release of insulin in response to glucose
• Also reduces appetite

Question 20

How is GLP-1 used therapeutically and what effect does it have on appetite upon administration ?

Answer 20

• Used as anti-diabetic medication or anti-obesity
• Lowers appetite

Question 21

1) Why must you use synthetic GLP-1 i.e. GLP-1 receptor agonists?
2) Name one such GLP-1 receptor agonist

Answer 21

1)

• Its rapidly degraded by DPP4 - has a very short half-life of one minute
• Synthetic versions will evade this degradation so will have a much higher half-life

2)

• Saxenda

Question 22

Where is ghrelin secreted from and what is its pattern of secretion?

Answer 22

• Secreted from the stomach
• Secretion decreases in post-prandially (after meals)

Question 23

Describe how ghrelin works and the processes involved for ghrelin to exert its physiological function

Answer 23

• Ghrelin is a 28 A.A protein with a F.A on serine at position 3
• GOAT = Ghrelin o-acetyl transferase transfers this F.A onto ghrelin
• Once this F.A is conjugated onto the ghrelin it can access the brain through the BBB where it has its effect
• It binds to receptors in the arcuate nucleus of the hypothalamus to stimulate NPY / AgRP and to inhibit POMC in order to inhibit MC4R in order to have its main physiological effect - increasing appetite

Question 24

1) What side effect can occur if you administer gut hormones by injection and how can you overcome this?
2) Even if you do this measure, how can this effect still be induced?

Answer 24

1)

• Induces nausea
• If you administer intravenously then this effect can be overcome

2)

• If you inject a high concentration in a ‘spike’ like fashion this can also induce nausea

Question 25

What do MZ twin studies say about the incidence of obesity?

Answer 25

There is a much higher incidence in identical than non-identical twins, suggesting genetic influence

Question 26

What are the 2 genetic theories for the genetics of obesity?

Answer 26

The thrifty gene hypothesis vs the adaptive drift ‘drifty’ gene hypothesis

Question 27

1) Describe the thrifty gene hypothesis for why people are genetically predisposed to become obese / get diabetes
2) What evidence exists for this?

Answer 27

1)

• Its evolutionarily beneficial to be able to make metabolism and fat storage effective in order to maintain fat stores to prevent starvation
• Therefore these genes were selected for

2)

• Populations historically prone to starvation put on the most weight upon exposure to the western obesogenic diet and sedentary life-style (e.g. Pima indians and Pacific islanders)

Question 28

Describe the adaptive drift ‘drifty’ gene hypothesis

Answer 28

• So, obviously there’s a normal distribution of weights
• There’s evolutionary costs of both high and low body weights - obese people are more prone to predation (struggle to escape predation) while thin people are prone to starvation
• However, as time went on and we developed the capacity to better defend against predation - with weapons etc, the evolutionary cost for being thin became greater than that of the now reduced evolutionary cost for being obese
• So there was a neutral shift towards those who are genetically predisposed to obesity - i.e shift in the normal distribution curve towards higher body weights