Obesity and the endocrine control of food intake

Question 1

what is the name of the key area involved in the regulation of food intake?

Answer 1

arcuate nucleus

Question 2

what allows the arcuate nucleus to carry out its function

Answer 2

Incomplete blood brain barrier, allows access to peripheral hormones.
It’s a circumventricular organ.
Integrates peripheral and central feeding signals.

Question 3

what are the two neuronal populations in the arcuate nucleus and what do they do?

Answer 3

Stimulatory (NPY/Agrp neuron). INCREASE APPETITE

Inhibitory (POMC neuron): DECREASE APPETITE

both sets of neurons extend to other hypothalamic and extra-hypothalamic regions

Question 4

what are potential human CNS mutations affecting appetite?

Answer 4

No NPY or Agrp mutations associated with appetite discovered in humans.
POMC deficiency and MC4-R mutations cause morbid obesity

Question 5

what are the characteristics of the ob/ob mouse?

Answer 5

Recessive mutation. 
• Profoundly obese. 
• Diabetic. 
• Infertile. 
• Stunted linear growth. 
• Decreased body temperature. 
• Decreased energy expenditure. 
• Decreased immune function. 

Similar abnormalities to starved animals.

Question 6

what is leptin?

Answer 6

Discovered in 1994. •Codes for 167 amino acid hormone
•Missing in the ob/ob mouse.

-decreases appetite

Question 7

what does leptin do?

Answer 7

Low when low body fat High when high body fat
•Central or peripheral administration decreases food intake and increases thermogenesis.
•Activates POMC and inhibits NPY/AgRP neurons.

Question 8

why is leptin ineffective as a weight control drug?

Answer 8

Leptin circulates in plasma in concentrations proportional to fat mass.
• Most fat humans have high leptin.
• Obesity due to leptin resistance hormone is present but doesn’t signal effectively.

Question 9

what other effects can leptin lead to?

Answer 9

Absence of leptin has profound effects, including hyperphagia, lowered energy expenditure, sterility.

However, leptin is an anti-starvation hormone rather than anti-obesity hormone.

Presence of leptin tells the brain that one has sufficient fat reserves for normal functioningbut high leptin has little effect

Question 10

where are the leptin receptors?

Answer 10

hypothalamus

Question 11

how many different hormones does the gut release?

Answer 11

The gastrointestinal tract is the body’s largest endocrine organ. • Releases more than 20 different regulatory peptide hormones. • Influence processes including gut motility, secretion of other hormones, appetite. • Release regulated by gut nutrient content.

Question 12

what is ghrelin?

what does it modulate?

Answer 12

28aa gastric hormone
activated by Ghrelin O-acyltransferase ‘GOAT’, adding a fatty acid chain to its third aa

• Stimulates NPY/Agrp neurons.
• Inhibits POMC neurons.
• Increases appetite

Question 13

what cells secrete PYY and GLP-1

Answer 13

L-cells

Question 14

what does PYY do?

Answer 14

Inhibits NPY release.
• Stimulates POMC neurons.
• Decreases appetite.

Question 15

what is GLP-1?

Answer 15

Glucagon-like peptide-1
Gut hormone coded for by the preproglucagon gene and released post-prandially.

Well characterised incretin role in stimulating glucose-stimulated insulin release and also reduces food intake

Question 16

What is saxenda?

Answer 16

Long-acting glucagon-like peptide-1 receptor agonist (liraglutide) from Novo Nordisk.

Double the dose used for T2DM. Approved by FDA in 2014 and EMEA in 2015

Question 17

gut hormones: what are the three types of satiety action?

Answer 17

Post-prandial Reduces food intake following a meal

Chronic Gut disease – chronic elevation suppresses appetite

Acute nausea Toxin ingestion – acutely very high levels

Question 18

what comorbidities are associated with obesity?

Answer 18

depression
sleep apnoea
bowel cancer
peripheral vascular disease
gout
MI
stroke 
hypertension 
diabetes

Question 19

what is the thrifty gene hypothesis?

Answer 19

• Specific genes selected for to increase metabolic efficiency and fat storage. In the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes
• Evolutionarily sensible to put on weight.
• Thin humans didn’t survive famines, so didn’t pass their genes on to modern humans

Question 20

what is the adaptive drift hypothesis?

Answer 20

Normal distribution of body weight: the fat are eaten, the thin starve.
• 10-20K yrs ago, humans learned to defend against predators.
• Thus obesity not selected against.
• Putting on body fat then a neutral change (genetic drift). (though unlikely to put on much weight).
• In current context, the inheritors of these genes become obese.