Anti-Obesity Agents

Question 1

List the different ways of combatting obesity

Answer 1

Reducing caloric intake - dietary modification
Reducing calorie intake from specific foods - nutrient sequestering or preventing uptake
Creating a natural calorie deficit - excercise
Creating an artificial calorie deficit - Uncoupling calorific intake from ATP production
Reduce food consumption - Supress hunger

Question 2

Describe how to use pharmacological agents to uncouple calorific intake from ATP production and the effects of this

Answer 2

Use 2,4-DNP to act as ionophore so that H ion concentration gradient across the mitochondrial membrane equilibriates and no oxidative phosphorylatin leading to ATP production. The thermogenesis from this leads to severe hyperthermia and even death - hence it is no longer used

Question 3

Describe how fats are absorbed in the body

Answer 3

They help with fat soluble vitamin absorption. Emulsified by amphiphilic bile acids which form micelles, solubilising insoluble lipids. This leads to increased hydrolysis by lipase enzymes due to increased surface area. Lipases from pancreas hydrolyse triglycerides into glycerol and free fatty acids by cleavage of ester bonds - lipolysis. These can then cross the membrane of the lumen and enter the enterocytes lining the gut epithelium. They then get combined into triglycerides again, and combined with apolipoproteins and packaged into chylomicrons (micelles) for transport to liver etc.

Question 4

Describe how pharmacological agents can be used to stop the absorption of fats from food and how this helps obesity

Answer 4

Orlistat inhibits the lipase enzymes which metabolise triglycerides, meaning they can’t leave the GI and pass out through faeces. Orlistat is a suicide inhibitor (mechanism-based), meaning it uses itself up in the process. The inhibition is irreversible as it forms covalent bonds with serine in the active site of the lipase. Orlistat is highly specific for lipases. The absorption of orlistat into the systemic circulation is negligible, and this is good because the action is needed in GI, and if the inhibitor was to go anywhere else it would be less effective in the target area. Also, it may interfere with other enzymes.

Question 5

Describe how pharmacological agents can be used to reduce appetite

Answer 5

We can use an antagonist or an inverse agonist of the cannabinoid receptor to suppress hunger. Rimonabant was the first CB1 inverse agonist. An inverse agonist has the opposite effect of an agonist. However, due to it being a depressant, it resulted in many mental health issues and suicides so targetting CB1 for weight loss has been halted.