Obesity Flashcards
What is obesity?
Excess fat accumulation to the extent that it may have an adverse effect on health.
BMI equation?
Weight (kg)/height (m)^2
Is BMI accurate?
Not entirely - use waist measurements too.
Explain different BMI figures and what they indicate.
30 - obese
>40 - morbidly obese.
What does obesity increase your risk of.
1.6 x stoke
2.9 x BP
20 x diabetes mellitus.
What are some of the consequences and implications of being obese?
Increased body size - effects on joints and less likely to wear a seatbelt.
Increase fatty acids in the blood - insulin resistance (diabetes).
Proinflammatory state ( increase risk of thrombosis).
Fat is a source of oestrogen after menopause - increase in oestrogen responsive tumors.
MASSIVE ECONOMIC COST.
Name 4 causes of obesity.
Sedentary lifestyle.
Hedonic eating.
Time delays in satiety system.
High calories in modern processed food - stomach can be just half full with a massive number of calories.
What leads to weight loss?
Decreased calorie intake and increased exercise.
Who should, according to NIH and NHS, be treated for obesity?
NIH: BMI >30 or BMI >27 with co-morbidity.
NHS: Adults who have lost 2.5kg by diet alone and are BMI >27 with comorbidity or BMI >30.
Aims of obesity treatment?
A SUSTAINED reduction in body weight of 5% can decrease the risk of obesity related CV disease and diabetes.
5% placebo adjusted decrease in weight loss is the minimum threshold for approval in guidelines issued by regulatory authorities.
Although clinicians and patients desire a greater efficacy of 10% weight loss.
Name 3 possible mechanisms to target obesity.
1) Suppress appetite.
2) Inhibit nutritent uptake
3) Stimulate metabolic rate (but problem of compensation and that the body is made to prevent weight loss).
What endogenous molecules inhibit appetite?
Leptin, PPY, Insulin
What endogenous molecules make you feel hungry?
Grehlin
What are the 2 sets of neurones in the arcuate nucleus?
POMC/CART - decrease appetite and metabolism.
NPY/AGRP - have opposing effects.
Activation of one set of neurones inhibits the other.
Explain leptin.
Produced by adipocytes.
Acts via receptor in hypothalamus to reduced energy intake.
LEPTIN DEFICENCY CAUSES OBESITY.
Leptin with the leptin receptor activations POMC converted to aMSH by prohormone convertase1 (PC1)
aMSH to MC4 and 3 R…downstream signalling leads to decreased food intake and increased metabolic rate.
Could leptin be a potential target for treating obesity?
Not really…
Obese patients have high leptin levels - leptin is ineffective in hedonistic feeding.
Leptin resistance.
Leptin penetration through BBB decreases in obesity.
Could pathways downstream of leptin be potential targets for treating obesity?
No known method to increase POMC. (and also SE due to POMC derived peptide - eg adrenal)
PC1 - involved in too many other functions in the body.
MC3/4R are potential targets (MC4R increases penile erection)
Could insulin be used in the treatment of obesity?
Produced by beta cells in pancreas in response to nutrient intake.
Centrally reduces energy intake.
Peripherally increases weight gain…
Many diabetic drugs increase weight.
- insulin signals in brain make you feel full BUT
- insulin signals in mass make you increase fat mass.
Unless you inject into the brain - it’s no good!
Could you inhibit NPY neurones?
NPY increase food intake.
Ghrelin stimulates NPY neurones therefore BLOCK GHRELIN.
PYY inhibit NPY neurones - USE THIS PATHWAY.
Explain how blocking Ghrelin might work.
ghrelin is the only orexigenic hormone (from the stomach).
BUT levels are low in obese patients - and it rises with weight loss - therefore dieting is hard!
May prevent weight regains after weight loss by another method.
PYY pathway - explain how this could be utilised to treat obesity.
PYY produced by L cells in the intestine.
Reduces blood intake - binds to Y2 receptors on NPY neurones and decreases NPY release, GABA release and tehrefore increase POMC neurone activity.
BUT - a nasal spray was introduced by wasn’t efficacious enough!
Explain the 5HT action on the melanocortin pathway.
5HT activates POMC neurones.
5HT hyperpolarises and inhibits NPY/AGRP.
Stops inhibitory GABA transmission
Sibutramine - SNRI…/decrease apetite and increase satiety. Alter NPY POMC levels. May increase leptin transport into the brain.
Endocannabinoids
released in the presence of palatable food.
Act on CB1 receptors
Attenuate satiety signals - keep eating!
Rimonabant - CB1 antagonist…decrease body weight BUT withdrawn due to suicidal behaviour!
How could you inhibit nutrient uptake?
Orlisat - prevents uptake of fats. Inhibits lipase which breaks down fats in the diet to FA and uptaken into small intestine. So fat - faeces.
BUT unsociable side effects - abdominal crampls, flatulence and oily spotting.
How does phentamine work?
Increase release of NAdr.
Stimulate B receptors
Inhibit appetite.
how does Topiramate work?
Not sure!
How does Bupropion work?
Dependant on DA and NAergic signalling on POMC neurones.
How does naltrexone work?
Long acting opioid antagonist.
Treat alcohol and opioid dependance.
Acts synergistically with bupropion to release POMC neurones from inhibitory feedback mechanisms that limit their activity,
Liraglutide
GLP-1 agonist.
Suppressed appetite - overlaps with PYY pathway.
Decreases gastric emptying.
Conclusion of obesity treatments?
The perfect anti-obesity drug is ter to be developed.
