Obesity and the Endocrine Control of Food Intake

Question 1

What is balanced in body weight homeostasis?

Answer 1

Food Intake
Energy Expenditure

Eat more food than you’re expending energy = rise in body weight and vice versa

Question 2

What is the main organ which is involved in body weight homeostasis?

Answer 2

The hypothalamus

Question 3

How does the hypothalamus regulate body weight?

Answer 3

Has many inputs from hormones and organs from around the body which all influence its regulation of food intake (via hunger sensation etc) and energy expenditure

Question 4

What is the key area of the brain involved in the regulation of food intake?

Answer 4

Arcuate nucleus of the hypothalamus

Question 5

What is special structurally about the arcuate nucleus, what does this allow and does it integrate peripheral or central feeding signals or both?

Answer 5

Incomplete blood-brain-barrier

• this allows access to peripheral hormones (which regulate food intake)
• integrates BOTH peripheral and central feeding signals

Question 6

What are the two types of neuronal populations in the arcuate nucleus?

Answer 6

Stimulatory (NPY, Agrp neuron)

Inhibitory (POMC neuron)

Question 7

Which neurone types increase appetite?

Answer 7

Stimulatory - NPY/Agrp neurones

Question 8

Which neurone types decrease appetite?

Answer 8

Inhibitory - POMC neurones

Question 9

To where do both inhibitory and stimulatory neurones extend?

Answer 9

Extend to other key parts of the hypothalamus involved in appetite regulation and extra-hypothalamic regions

Question 10

What is the name of the receptor that reduces appetite when stimulated and where is it found?

Answer 10

MC4R

- found in the paraventricular nucleus (arcuate and paraventricular nuclei are in contact)

Question 11

How are the arcuate nucleus, the paraventricular nucleus, and the MC4Receptor involved in regulating food intake?

Answer 11

The arcuate nucleus contains two types of neurones: POMC (appetite-decreasing) neurones and Agrp (appetite-increasing) neurones.

• When the POMC neurones are activated, they release a peptide hormone called alpha-MSH which travels to the paraventricular nucleus, where MC4R are found. When alpha-MSH binds to MC4R, it stimulates it and MC4R reduces appetite when stimulated thus reducing food intake.
• When the Agrp neurones are activated, they release Agrp which travels to the paraventricular nucleus. However, when it reaches the MC4R, it actually inhibits the receptor which prevents the receptor from reducing appetite, thus overall INCREASING food intake.

Question 12

What do POMC deficiency and MC4-R mutations cause?

Answer 12

Morbid obesity

• very rare cause of obesity but it is possible
• if POMC and MC4-R are problematic then appetite is never reduced so continually hungry

Question 13

Is the hypothalamus alone in regulating food intake?

Answer 13

No, quite the opposite dear Watson

• the hypothalamus is involved with numerous other brain regions
• also communicates with the Gut via the Vagus nerve and the brainstem, and slo communicates with adipose tissue

Question 14

What does a recessive mutation of the Ob gene cause? (seen in mice)

Answer 14

• Profoundly obese
• Hyperphagia (always eating)
• Diabetic (because of the hyperphagia)
• Decreased body temperature
• Decreased energy temperature

Question 15

What is Leptin?

Answer 15

It is a peptide hormone which signals how much fat store we have in our body

Question 16

Where is Leptin released from?

Answer 16

From fat

- white adipose tissue

Question 17

Where are receptors for Leptin found in the body?

Answer 17

Hypothalamus

- termed Ob-R(eceptors)

Question 18

What gene codes for the hormone Leptin?

Answer 18

The Ob gene (everything makes sense now dunnit!)

Question 19

So what is missing in humans/mice with an Ob gene mutation?

Answer 19

Leptin!

- no communication between the fat in their body and the hypothalamus to regulate food intake so permanently hungry

Question 20

When is Leptin high and low?

Answer 20

High when high body fat

Low when low body fat

Question 21

What does central or peripheral administration of leptin (by injection) cause?

Answer 21

Decreases appetite and food intake
- Increases thermogenesis (way of expending energy)

Decreases food intake
Increases energy expenditure

Question 22

How does Leptin interact with the arcuate nucleus (POMC/Agrp)?

Answer 22

Activates POMC neurones (stimulates MC4-Rs which reduces appetite)
Inhibits NPY/Agrp neurones (prevents increasing appetite)

Question 23

How effective is leptin as a weight control drug and why is this?

Answer 23

Ineffective

• leptin circulates in plasma at concentrations proportional to fat mass
• most obese humans have very high leptin and this is mainly due to their diet of high fat, high sugar diet
• past a certain point of obesity, the brain becomes resistant and unresponsive to leptin, so the hormone is present but doesn’t signal effectively

Question 24

What levels do insulin circulate at, where are receptors for insulin in the brain, and what does central administration of insulin cause?

Answer 24

• Insulin circulates at levels proportional to body fat
• receptors are in the hypothalamus (insulin is a peripheral hormone communicating centrally with the hypothalamus)
• central administration (into the brain) reduces food intake

Question 25

What is the largest endocrine organ in the body?

Answer 25

The GI tract!

Question 26

How many different regulatory peptide hormones are released in the GI tract and what is their release regulated by?

Answer 26

More than 20 | - released regulated by the content of nutrients found in the gut

Question 27

What processes are influenced by GI tract-secreted peptide hormones?

Answer 27

Gut motility Secretion of other hormones Appetite (important)

Question 28

What is Ghrelin also known as, what does it affect and where is it released?

Answer 28

'The Hunger Hormone' - increases appetite - released by the stomach

Question 29

When is Ghrelin high and low around meals?

Answer 29

High before meals (increases appetite) | Low after meals (appetite is 'satiated')

Question 30

How does Ghrelin affect neurones in the arcuate nucleus?

Answer 30

Directly modulates neurones in the arcuate nucleus - Stimulates NPY/Agrp neurones - Inhibits POMC neurones Overall increases appetite

Question 31

What interesting research did Imperial conduct on Ghrelin's effects?

Answer 31

Gave participants infusion of saline or ghrelin and assessed food intake after both. - both participant and instructor blinded - every single participant ate more on the day they were give Ghrelin compared with the day they were given Saline

Question 32

What hormones do L cells secrete and where are L cells found?

Answer 32

PYY GLP-1 - L cells are endocrine hormone-secreting cells found in the gut

Question 33

What is PYY also known as and what does it do?

Answer 33

Peptide-YY - the 'satiety hormone' - reduces appetite after we've eaten - induces the feeling of 'fullness'

Question 34

How does PYY work?

Answer 34

OPPOSITE OF GHRELIN Directly modulates neurones in the arcuate nucleus - inhibits NPY/Agrp neurones - stimulates POMC neurones Overall decreases appetite

Question 35

What did the results in a study assessing the effect of PYY show?

Answer 35

Opposite effect to ghrelin - all 12 volunteers ate less food after PYY injection compared with the control - reduced food intake by 36%

Question 36

What is GLP-1, where is it released, what is it coded for and when is it released?

Answer 36

Glucagon-like Peptide-1 - Released in the gut - coded for by the PREPROGLUCAGON gene (some of which codes for glucagon itself) - released post-prandially (after eating)

Question 37

What type of hormone is GLP-1 and what effect does it have on appetite?

Answer 37

``` An Incretin (has good incretin characteristics, augments insulin secretion well) - Reduces appeitite ```

Question 38

What are Incretins?

Answer 38

Hormones that - are released after eating - augment insulin secretion from beta islet cells

Question 39

Thinking on the effects of incretins, what can GLP-1 be used to treat?

Answer 39

Diabetes! | - pharmacological mimicry of GLP-1 enhances insulin release which helps treat the diabetes

Question 40

What is DPP-4?

Answer 40

DPP-4 is a peptide enzyme which breaks down GLP-1

Question 41

What is the purpose of DPP-4 inhibitors and what is the main benefit to the patient of these drugs over GLP-1 agonist injection?

Answer 41

Inhibit DPP-4 enzymes preventing breakdown of endogenous GLP-1 (boosts GLP-1 effect) - main benefit is they can be given orally whereas GLP-1 agonists must be injected, sometimes multiple times a day which is unpalatable enough to some patients that they can't follow the treatment plan

Question 42

Why must GLP-1 agonist analogues be developed to be resistant to breakdown?

Answer 42

Endogenous GLP-1 only has a half-life of around 1 minute before it is inactivated by DPP-4 - any drugs that mimic GLP-1 must be resistant to breakdown in order to have enough of an effect that the patient doesn't constantly have to inject it

Question 43

What is Saxenda?

Answer 43

Saxenda (liraglutide) is a long-acting glucagon-like peptide-1 receptor AGONIST - reduces appetite - enhances insulin release close to the degree of effect of endogenous GLP-1

Question 44

Why is PYY not a good drug target?

Answer 44

In studies, when levels of PYY goes too high, it can induce strong nausea and vomiting - even with GLP-1 analogues, which are FDA licensed for treatment of diabetes, patients have to be warned of nausea that should usually settle over the first couple weeks

Question 45

Why is obesity a problem, from a medical perspective?

Answer 45

Obesity is associated with numerous severe co-morbidities (predisposition to severe clinical problems)

Question 46

What is one major appearing clinical problem associated with obesity?

Answer 46

Depression | - both due to their own views on their body and societies pressures and ideals

Question 47

What is the 'thrifty gene hypothesis'?

Answer 47

Hypothesis that when we were cavemen, specific genes were selected for to increase metabolic efficiency and fat storage. In the context of plentiful and easily available food and little exercise, these genes predispose their carriers to obesity and diabetes - evolutionary sensible to put on weight and store energy as fat in case of no dinner - thin humans didn't survive famines so didn't pass on their genes to modern humans

Question 48

Where is the evidence for the 'thrifty gene hypothesis'?

Answer 48

Populations historically prone to starvation become the most obese when exposed to Western diet and sedentary life-style (e.g. Pima Indians, pacific islanders)

Question 49

What is the question that highlights the problem with the 'thrifty gene hypothesis'?

Answer 49

Why aren't we all overweight if we all have these genes?

Question 50

What is the alternate hypothesis to the 'thrifty gene hypothesis'?

Answer 50

``` Adaptive drift ('drifty gene') hypothesis - idea is that there is a normal distribution of body weight where the most obese can't run away so are eaten and the leanest die during famine ``` (SEE THE SLIDES IN NIAMH'S PRESENTATION WHICH EXPLAIN THIS FULLY)

Question 51

As a general consensus between the two hypotheses, what drives obesity?

Answer 51

The effects of the environment on the genetic background - everyone is affected different due to genetic variation but some will be affected more than others as their background both promotes this directly (large availability of unhealthy food and sedentary lifestyle) or indirectly (genetically predisposes people to becoming obese when exposed to the correct environment)