14. Obesity and Endocrine Control of Food Intake Flashcards
Main controlling component of body weight homeostasis
The hypothalamus- all inputs come into the hypothalamus
Hypothalamus anatomy (relevant to food intake)
The key brain area that is involved is the ARCUATE NUCLEUS- a circumventricular organ (has an incomplete blood-brain barrierallowing access to peripheral hormones)
TWO main neural populations:
- Stimulatory- NPY+AGRP neurones
- Inhibitory- POMC neurones
Both sets of neurones extend to other hypothalamic and extra-hyothalamic regions
Melanocortin system of apetite control
- Under normal condtitions, the POMC will be broken down to a-MSH
- a-MSH is an endogenous agonist of MC4R
- We are not hungry all the time du to the a-MSH tone
- To trigger hunger we release Agrp from the arcuate nucleus which is an endogenous antagonist of MC4R
Human CNS mutations affecting appetite
There are NO NPY or AGRP mutations associated with appetite discovered in humans
- POMC deficiency (red hair+ very pale) and MC4R mutations cause morbid obesity
Ob/ob mutation (in mice)
This causes LEPTIN DEFICIENCY:
- Recessive mutation
- Profoundly obese
- Diabetic
- Infertile- body switches off reproductive axis
- Stunted growth
- Decreased energy expenditure and immune function
- Similair abnormalities to starved animals
Leptin action and resistence
Leptin is generated from white adipose tissue- has Ob-R receptors in the hypothalamus
Central of peripheral administration of leptin will decrease food intake and increase thermogenesis
- leptin activates POMC and inhibits NPY/Agrp neurones
Leptin resistence means taht it is innefective as a weight control drug:
- Has effects such as hyperphagia, lowered energy expenditure and sterility
- Without leptin, people will not go through puberty- Leptin has a permissive effect on GnRH so none will be released
LEPTIN IS MORE OF AN ANTISTARVATION HORMONE THAN AN ANTIOBESITY ONE (high leptin has little effect)
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
Effect of insulin when it crosses the blood-brain barrier
- Chronically- reduces body fat
- Acutely- a big glucose load will lead to insulin release which will lead to food intake supression
It is difficult to seperate the effects of insulin on food intake from the effects of insulin on blood glucose
Main Important Gut Hormones
- Ghrelin
- PYY
- GLP-1
Body’s largest endocrine gland
GI tract- releases more than 20 different regulatory peptide hormones which influences motility, secretion and appetite
Release is regulated by nutrient content
Ghrelin action
Ghrelin is a hunger hormone released by the stomach
- Has a fatty acid on the 3rd amino acid along
- Converted to its active form by Ghrelin O-Acyltransferase (GOAT)
- Its levels are high in the morning, then decrease after breakfast, then rise until lunch etc.
- Increases appetite by directly modulating neurones in the arcuate nucleus:
- Stimulates Agrp/NPY neurones
- Inhibits POMC neurones
PYY and GLP-1 action
PYY and GLP-1 are secreted by L-cells (in the distal small intestine and colon)
Towards the apical side of the cell is sensory equipment giving information on the contents of the lumen
PYY
- PYY is a ‘fullness’ hormone released Post-prandially (after meal)
- Release is dependant on the size of the meal
- Decreases appetite by INHIBITING NPY release and STIMULATING POMC neurones
GLP-1
- Gut hormone coded for by the preprogucagon gene, formed by pro-glucagon processing in L cells
- Has a well characterised incretin role: it stimulate glucose-induced insulin release and also reduces food intake
- GLP-1 based drugs are important in the treatment of diabetes-melitus- stimulates glucose induced insulin release (i.e only when needed)
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 (GLP-1) that potentiate the effects of glucose-induced insulin release
Saxenda
Long-acting GLP-1 receptor agonist (more resistent to degredation) can be used as a treatment for diabetes and obesity as well as weight loss
Why saxenda is prefered to PYY3-36
Saxenda has a longer therapeutic window due to the prescence of its fatty acid, making it more resistent to degredation
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 PYY cuases nausea
