Appetite

Question 1

• Draw a simple diagram to summarise how the hypothalamus regulates appetite.

Answer 1

Body Weight Homeostasis

• All the inputs come into the hypothalamus
• Then the hypothalamus decides whether you should be eating or not

Question 2

Recall the main neuronal populations involved in the regulation of appetite.

Answer 2

The endocrine control of food intake

• The hypothalamic regulation of appetite • Leptin and insulin
• Gut hormones
• The reasons for obesity

Hypothalamus Anatomy:

• The ARCUATE NUCLEUS is the key brain area that is involved in regulation of food intake
• It is a circumventricular organ meaning that it has an incomplete blood-brain barrier thus allowing access to peripheral hormones
• This allows the arcuate nucleus to integrate peripheral and central feeding inputs
• There are TWO neuronal populations:
  
  • Stimulatory K NPY + Agrp neurons
  • Inhibitory K POMC neurons
• So NPY and Agrp INCREASE appetite
• POMC DECREASES appetite
• Both sets of neurons extend to other hypothalamic and extra-hypothalamic regions

Question 3

• Explain how mutations disrupting these neural systems can influence energy balance.

Answer 3

Human CNS mutations affecting appetite

NO NPY or Agpr mutations associated with appetite discovered in humans

POMC deficiency and MC4-R mutations cause morbid obesity:

• POMC deficiency is associated with having RED hair
• People who are POMC deficient also tend to be very pale
• MC4R mutations are more specific -> it is basically only about food intake
• People with an MC4R mutation don’t have the same hair and skin coloration changes but they will be massively obese

This isn’t what’s causing most obesity - but useful to explain signaling in monogenic obesity.

Question 4

Explain the role of leptin in energy homeostasis and reproduction

Answer 4

The ob/ob mouse

• Recessive mutation
• Profoundly obese.
• Diabetic.
• Infertile.
• Stunted linear growth.
• Decreased body temperature.
• Decreased energy expenditure
• Decreased immune function.
• Similar abnormalities to starved animals
• Aside from the obesity and diabetes, the other aspects are similar to a model of STARVATION
• If you are starving you switch off the reproductive axis because if you barely have enough body fat for yourself then you shouldn’t be having kids
• There is also a decrease in immune function because the immune system is energy consuming and is a luxury -> so in the situation of low energy intake it is compromised

Leptin

• Codes for a 167 amino acid hormone
• This is missing in the ob/ob mouse and is missing in leptin deficient humans
• Leptin is released from fat and tells the brain how much fat there is in storage thus regulating eating
• People who are leptin deficient will think they are starving all the time because there isn’t any leptin to tell the brain that there are fat stores
• Central or peripheral administration of leptin will decrease food intake and increase thermogenesis
• Leptin activates POMC and inhibites NPY/Agrp neurones

Leptin Resistance

• Leptin circulates in plasma in concentrations proportional to fat mass
• Most fat humans have HIGH leptin
• So a lot of obese people are leptin resistant -> the hormone is there but it doesn’t signal effectively
• This means that leptin is ineffective as a weight control drug
• Absence of leptin has profound effects including hyperphagia, lowered energy expenditure and sterility
• People with leptin deficiency will respond well to leptin therapy
• Without leptin, they will not go through puberty
• The hypothalamus won’t be releasing GnRH because leptin has a permissive effect on GnRH release
• If you inject someone with leptin deficiency with leptin, you can restore the pulsatile release of LH and FSH
• Similarly, a big cause of amenorrhoea is low body weight
• You can make these people start having periods again by giving leptin -> it gives the illusion of having sufficient body fat
• NOTE: leptin is more of an anti-starvation hormone than an anti-obesity hormone
• Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning but high leptin has little extra effect

Question 5

Describe the role of gastrointestinal hormones in the regulation of food intake, and their interaction with the central neural systems that control appetite

Answer 5

Role of Insulin in Food Intake

• Insulin circulates at levels that are proportional to body fat
  
  • This may be partly due to the fact that fat people are more likely to be insulin resistant so more insulin is needed
• There are insulin receptors in the hypothalamus
• Insulin signals in a similar way to leptin
• Central administration of insulin reduces food intake Insulin may coordinate glucose and energy homeostasis

Although insulin will go up and down related to what you are eating - it sometimes correlates with body fat

• Peripherally, insulin does all the things we already know about with regards to maintaining constant blood glucose
• Insulin can also cross the blood9brain barrier and have different effects:
  
  • Chronically: reduce body fat
  • Acutely: if you have a big glucose load, you should suppress having more sugar
• It is difficult to separate the effects of insulin on food intake with the effects of insulin on blood glucose - but it does seem to be related to fat deposition

Question 6

Explain the effects of ghrelin and glucagon-like peptide on food intake

Answer 6

Gut Hormones

• GI tract is the body’s largest endocrine gland
• It release more than 20 different regulatory peptide hormones
• It influences processes including gut motility, secretion of other hormones and appetite
• Release is regulated by gut nutrient content
• Paracrine, or endocrine effects

Important Gut Hormones

1. Ghrelin: hunger hormone

• Released by the stomach
• It is 28 amino acids long
• There is a fatty acid on the 3rd amino acid along
• It is converted to the active form by Ghrelin OK Acyltransferase (GOAT)
• It is high in the morning and then goes down after breakfast and rises again until lunch (it drops after every meal and then slowly rises)
• Ghrelin INCREASES appetite by directly modulating neurones in the arcuate nucleus:

1. ### STIMULATES Agrp/NPY neurone
2. ### INHIBITS POMC neurones

• Ghrelin increases food intake in humans: if you get someone who has just had a meal, you can trick them into feeling hungry by giving ghrelin

2. PYY and GLPK1

• Both PYY and GLP91 are secreted by the LK cells
• When you get to the L cells in the distal small intestine and colon they all co-secrete PYY and GLP91
• L cells have a distinctive flask shape
• (The yellow and red dots at the bottom show the hormone-containing granules)
• The finger of cytoplasm is going to have the sensory equipment to tell the cell what is going on in the lumen
• PYY 3936 is a fullness hormone that is release post-prandially
• The amount of PYY released is dependent on the size of the meal (the more calories you eat the more PYY is released)
• PYY₃₉₃₆ DECREASES appetite by directly modulating neurones in the arcuate nucleus:

1. ### INHIBITS NPY release
2. STIMULATES POMC neurons

• PYY₃₉₃₆ and Ghrelin have more or less opposite effects on the arcuate nucleus
• So PYY can reduce the appetite of hungry people

PYY 3-36 reduced food intake by 36%

3. GLPK1 - Glucagon-like peptide-1​

• This is a gut hormone coded for by the preproglucagon gene and release post-prandially
• Pro-glucagon (product of preproglucagon) in L9cells is processed in such a way that you release GLP91
• GLP91 has a well characterised incretin role in stimulate glucose-induced insulin release and also reduces food intake
  
  • Incretin Effect: if you give someone oral glucose you get a much bigger rise in insulin than if you give them the same amount of glucose IV. This is because glucose travelling in the GI tract stimulates the release of hormones that potentiate the effects of glucose-induced insulin release
  • (incretins one of which is GLP1)
• GLP91 based drug are important in the treatment of diabetes mellitus
• GLP91 only stimulates glucose9induced insulin release which is good because it means that it only stimulates insulin release when it’s needed
• If it was stimulating insulin release all the time it would cause hypoglycaemia
• REMEMBER: GLPK1 REDUCES FOOD INTAKE
• Degradation of GLP91:
• GLP91 is quickly inactivated by DPK4 (dipeptidyl peptidase 4)
• So you have altered the drugs so that they have a longer half-life

Question 7

GLPK1 related medications

Answer 7

Gut Hormones- three types of satiety action

1. Post-prandial Reduces food intake following a meal
2. Chronic Gut disease – chronic elevation suppresses appetite
3. Acute nausea Toxin ingestion – acutely very high levels

Only a specific spectrum in which it is useful and doesn’t have akraia characteristics

Saxenda

• Long-acting GLP91 receptor agonist (liraglutide) from Novo Nordisk
• The structure of GLP91 has been tweaked so it is more resistant to degradation
• It also has a fatty acid group attached which stops it from being cleared from the circulation giving it a much longer half9life
• Saxenda has recently been approved by the FDA and EMEA as a treatment for diabetes and obesity
• Saxenda can cause pretty decent weight loss

PYY3K36 as a drug target

• If you inject someone with PYY, you will get a big, transient increase in drug concentration and then a relatively rapid drop
• At high levels, it will cause nausea
• There is a relatively small sweet spot in terms of drug concentration that gives the effects you want
• What you’re looking for is something that will get you into the good zone in terms of drug concentration and remains at that level for quite a long time
• Saxenda does this by adding the fatty acid onto it, thus making it more resistant to degradation

Question 8

Demonstrate awareness of theories that aim to explain the causes of the obesity epidemic in the context of the homeostatic control of energy balance

Answer 8

Obesity is associated with comorbidities

More on Obesity

• To a large degree, genetics dictate how obese you are going to be
• Heritability of body weight is about 60K80%

Thrifty Gene Hypothesis

• Thin people didn’t put on much weight and didn’t carry excess fat during the times when food was scarce so they didn’t survive and didn’t pass their genes on
• The greedy people did pass their genes on
• This suggests that we have an evolutionary drive to put on weight

Adaptive Drift (drifty gene) Hypothesis

• There used to be a normal distribution of body weight
• The ones that were too light will die/not be able to reproduce
• The ones that were too heavy would get eaten
• Eventually, we got better at defending against predators and so excess bodyweight became a neutral change

General Notes on Obesity

• Some people are genetically prone to become obese and some are genetically resistant