Endocrinology 14 - Obesity and Endocrine Control of Food Intake Flashcards
Describe the hypothalamic regulation of body weight
- Ghrelin, PYY and leptin input
- Neural input from the periphery and other brain regions
- Regulates food intake and energy expenditure (HR.ect)
Which areas of the brain are important in food regulation?
Arcuate nucleus or infundibular nucleus
What is the function of the arcuate nucleus?
- Involved in regulation of food intake
- Integrates peripheral and central feeding signals (incomplete blood brain barrier)
- Contains stimulatory (NPY/Agrp) and inhibitory (POMC) neurons
- NPY/AGRP neurons increase appetite
- POMC decreases appetite by conversion to a-MSH
List the human CNS mutations affecting appetite
- No NPY or AGRP mutations
- POMC and MC4-R mutations cause morbid obesity
- POMC deficiency is characterised by paleness and ginger hair
- Not responsible for the prevalence of obesity
What is the function of leptin?
- High when there is high body fat, and low when there is low body fat
- If leptin deficient, you will be in a starvation state and have increased appetite despite obesity
- Central or peripheral administration decreases food intake and increases thermogenesis
- Activates POMC and inhibits NPY/AgRP neurons
Describe leptin resistance
- Leptin circulates proportional to fat, so most fat humans have high leptin
- Obesity is due to leptin resistance - the hormone is present but does not signal effectively
- High leptin has little effect - leptin is meant to be a anti-starvation hormone
- Therefore, leptin is ineffective as a weight control drug
List the effects of absence of leptin
- Hyperphagia
- Lowered energy expenditure
- Sterility (lack of fertility)
What is the role of insulin in food intake?
- Insulin circulates at levels proportional to body fat
- Receptors in the hypothalamus
- Central administration reduces food intake
- Reduced food intake and increase glucose uptake by muscle
List the major gut hormones
- Cholecystokinin (gallbladder contraction, GI motility, pancreatic exocrine secretion)
- Secretin (pancreatic exocrine secretion)
- GIP (incretin)
- Motilin (GI motility)
- Ghrelin (hunger and GH release)
- Insulin and glucagon
- Pancreatic polypeptide (GI motility)
- Amylin (GI motility, glucose homeostasis)
- GLP1 (incretin activity and satiation)
- GLP2 (gut motility and satiation)
- Oxyntomodulin (salivation and acid secretion)
- PYY (satiation)
How does ghrelin affect the arcuate nucleus?
- Stimulates NPY/Agrp neurons (hunger neurons)
- Inhibits POMC (neurons that make you feel full)
- Increases appetite
Which cell type secretes PYY and GLP-1?
L cells (flask shape, thin part projects to the lumen and is sensory)
What is the effect of PYY on the arcuate nucleus?
- Inhibits NPY release
- Stimulates POMC neurons
- Decreases appetite
When is glucagon like peptide 1 released? What is it coded for by?
Post-prandially, quickly inactivated
coded for by preproglucagon gene - precursor molecule for glucagon
What is the role of glucagon like peptide 1?
- Incretin role - stimulates glucose-stimulated insulin release
- Reduces food intake
- Used clinically - analogues as it has a very short half life)
What is saxenda?
- GLP-1 receptor agonist, long acting
- Used for T2DM and obesity (higher dose for obesity)
List the three types of satiety action in gut hormones
- Post-prandial (reduces food intake following a meal)
- Chronic (chronic elevation suppresses appetite)
- Acute nausea (toxin ingestion - acutely very high levels)
List the comorbidities associated with obesity
- Depression
- Stroke
- MI
- Hypertension
- Diabetes
- Peripheral vascular disease
- Gout
- Osteoarthritis
- Bowel cancer
- Sleep apnoea
- Depression
What is the thrifty gene hypothesis?
- Specific genes selected for to increase metabolic efficiency and fat storage
- In the context of plentiful food and little exercise, this predisposes carriers to obesity and diabetes
- Thin humans wouldn’t survive famines, so could not pass on their genes
What is the adaptive drift hypothesis?
- Normal distribution of body weight - fat are eaten and thin starve
- Humans learned to defend against predators, so obesity was no longer selected against.
- Genetic drift to higher body weight, still normal distribution
What can leptin adminsitration be used to treat?
- Patients with no leptin production/ mutations in leptin
- Restores LH and FSH pulsatility as it prevents the body entering starvation state
How does the release of hormones in response to food occur? What is the effect?
- Enteroendocrine can sense fats, carbohydrates and protein (products of protein metabolism such as amino acids) via receptors on the apical surface
- Combintation of GI hormones released
- This results in paracrine effects (adjacent tissues), modulation of neuronal function and endocrine effects
What is ghrelin?
- 28 amino acid gastric hormone
- Ghrelin O-acyltransferase attaches a fatty acid to it, which can modulate its activity
Compare satiation and satiety
- Satiety is how long it is until your next meal
- Satiation is when you stop eating your current meal
What is the issue with the short half life of gut hormones in treatment?
- Fine therapeutic window
- Higher dose given which causes nausea, then a quick decrease to result in no effect
