Lecture notes from Imperial College London, Medical Biosciences BSc, 2nd year, pharmacology module.
Phar 9 on obesity: In this session, we will turn our attention to a different challenge: pharmaceuticals for treating obesity. We will start by defining what we mean by the term obese, before cons...
Obesity
What is obesity?
- in general = excess of adipose tissue from an imbalance between intake & consumption of calories
=> risk of comorbidity: risk factor for cardiovascular disease, diabetes, cancer...
Body Mass Index
- in clinic, obesity = BMI > 30 (overweight if 25<BMI<30)
- BMI = mass (kg)/ height^2 (m)
- easy to calculate + correlate reasonably with adiposity
BUT don’t take fat-to-muscle proportions into account
=> waist-hip ratio (WHR)
=> waist circumference (WC)
=> skin fold thickness
=> measure body fat percentage (BFP) but difficult
- ≠ location of fat: visceral fat (centrally, around organs)/ peripheral fat (around wait & limbs)
=> ‘apple’ body shape (common in men)
=> ‘pear’ body shape (common in women)
Body Weight Regulation
- adipocytes = cells that store fat in adipose tissue (with some fibroblasts & immune cells)
=> with obesity, increase in size (hypertrophy) & increase in number (hyperplasia)
=> can increase capacity up to 4-fold => weight change
- fat stored as triglycerides (TAGs) and cholesterol esters
- adipose tissue release adipokine => signaling proteins for E balance & eating behaviours
=> leptin: produced continually (constant in long-term)
=> increased adiposity promotes leptin release
=> defective/ missing/ resistant leptin => obesity
=> leptin administration associated with weight loss (reduce food intake)
- ghrelin: secreted by stomach when empty: promotes hunger & adipose fat formation (oscillatory)
increase food intake
, - hormones along the gut-brain axis regulate satiation (feeling while eating: reduces the impulse to
consume more)/ satiety (feeling of being sufficiently full of food after a meal: prevents further food
being consumed) and hunger
- hypothalamus integrates signals: arcuate nucleus contains 2 set of neurons
=> POMC/ CART: suppress appetite = anorexigenic
=> NPY/ AgRP: promote appetite = orexigenic
Antiobesity Agents I
- reduction in calorie intake (dietary restriction/ modification)
- reduction of calorific intake for specific foods (nutrient sequestering): Orlistat.
- create a natural calorific deficit (activity or exercise routing modification): most sustainable => better
- create an artificial calorific deficit (decouple calorific intake from ATP production): DNP
- reduce food consumption (suppress hunger/ desire to eat)
- artificial calorific deficit: drug 2,4-dinitrophenol (DNP)
=> uncoupler of oxidative phosphorylation acting as an ionophore (bind ions)
=> enable equilibration of H+ ions across mitochondrial membrane (H+ pumped back into matrix)
=> prevents generation of chemiosmotic gradient of H+ (proton-motive force)
=> no production of ATP by ATP synthase
=> increased E demand => weight loss
- DNP dangerous: uncoupling (unused potential E) result in hyperthermic DNP + no enough E => death
- fats (E-rich biomolecules): high levels in meat, processed foodstuff... => high calorific intake
(fat is healthy : provide E substrates + helps absorption of fat-soluble vitamins (A, D, E, K))
- fats emulsified by bile acids (amphipathic)
=> form micelles that solubilise insoluble lipids
=> larger surface for lipases to access
=> hydrolyse TAGs in intestinal lumen
=> form glycerol and free fatty acids: lipolysis
=> cross plasma membrane by passive diffusion & are absorbed into enterocytes
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