PHAR6: Obesity Flashcards
What does obesity mean?
An excess of adipose tissue, often as a result of calorific intake and lack of exercise
How do you calculate BMI?
BMI = mass(kg)/(height(m))^2
What BMI is considered overweight or obese?
Overweight = 25-30 Obese = 30+
Why is BMI not a good calculation of health?
it cannot account for the large differences in fat-to-muscle proportions people display
What other fat tests can be used?
- Other simple measurements used in studies are waist-to-hip ratio, waist circumference and skin fold thickness.
- A more representative measurement is body fat percentage, although this measurement is difficult to obtain.
Where can the different fat storage on the body be?
Around the organs = visceral fat (apple)
Around limbs and waist = peripheral (pear)
Which is more dangerous between peripheral and visceral fat? (Higher risk of comorbidity)
Visceral
What is the main component of adipose tissue?
Adipocytes
What are the words used to show increasing size and number of adipocytes?
Hypertophy = increase in size Hyperplasia = increasing number
How is fat in adipocytes normally stored?
Mainly triglycerides
Cholesterol esters
Adipocyte size can increase 4 fold (I thought it was 40?)
What are adipokines? And what are they responsible for?
Signalling proteins secreted by adipose tissue, they are responsible for cell signalling which regulates homeostasis and feeding
What does leptin do?
Involved in body weight regulation, it suppresses appetite.
What does Ghrelin do? When is it secreted?
Is secreted by the stomach when it is empty and promotes hunger
How is leptin produced? What does this mean about its blood levels?
Continually by the adipose tissue, therefore circulating levels are relatively constant over long periods of time
____________ adiposity promotes leptin release from adipocytes
Increasing
The changes in adiposity will ______ change over a short period of time (e.g. eating a meal)
Not
Leptin levels _____ with long term storage
Track
What type of pattern does ghrelin produce?
A more more frequently oscillatory pattern as is produced in response to an empty stomach
What is the central actor in the regulation of satiety?
The hypothalamus which regulates various signals
What two sets of neurones are on the arcuate nucleus
- POMC/CART
- NPY/AgRP
What do POMC/CART and NPY/AgRP do?
- POMC/CART: neurones that suppress appetite (inhibitory)
- NPY/AgRP: neurones that promote appetite and feeding behaviour (stimulatory)
What do anorexigenic and orexigenic mean?
Anorexigenic: suppress appetite
Orexigenic: promote appetite
What do you need to do to lose weight? How would you bring about these changes?
- reduction in overall calorie intake; dietary restriction or modification
- reduction in calorific intake from specific foods; nutrient sequestering or prevention of uptake
- create a natural calorific deficit; activity or exercise modification
- create an artificial calorific deficit; decouple calorific intake from ATP production
- reduce consumption of food; suppress hunger/desire to eat
What was the first drug used to control weight / increase weight loss?
2,4-dinitrophenol (DNP)
What does DNP do?
DNP is an uncoupler of oxidative phosphorylation; it acts as an ionophore that enables equilibration of H+ ions across the mitochondrial membrane.
How does DNP ccause weight loss by through increased energy demand?
DNP allows equilibration of the H+ across the mitochondrial membrane prevents sufficient gradient of H+, and therefore prevents the production of ATP from the phosphorylation of ADP, by ATP synthase in the last step of oxidative phosphorylation, a process driven by the proton-motive force (PMF; see Key Terminology) of H+ moving through the enzyme down the chemiosmotic gradient.
Why is DNP no longer used
It can be highly dangerous; thermogenesis from the uncoupling of phosphorylation can result in individuals exposed to DNP being severely hyperthermic and there are many cases of deaths resulting from the inadvertent or deliberate use of this compound
Where are fats absorbed?
GI tract but they must be emulsified first
How are fats emulsified?
By bile acids, which are amphipathic: Bile acids are able to form micelles that solubilize otherwise insoluble lipids, and critical in allowing efficient action of lipase enzymes that are able to hydrolyse the lipids in the intestinal lumen.
What does amphipathic mean?
They have both hydrophobic and hydrophilic domains in their structure
What enzymes are responsible for hydrolysing triacylglycerols (TAGs) in the intestinal lumen?
Pancreatic lipases secreted into the gut
How do pancreatic lipases hydrolyse TAGs?
Pancreatic lipases cleave the ester bonds TAGs contain to form glycerol and free fatty acids (FAs). This process is called lipolysis.
What are the name of the cells that line the gut epithelium?
enterocytes
How do monoacylglycerols and fatty acids cross the plasma membrane of enterocytes?
Passive diffusion
What happens to the monoacylglycerols and fatty acids once they have entered the enterocytes?
resynthesised into TAGs
What are the resynthesised TAGs combined with in the enterocytes before being packaged into micellar structures called chylomicrons
apolipoproteins
Describe the structure of chylomicrons
Triacylglycerides enclosed in a phospholipid envelope, containing apolipoproteins.
What is the purpose of lipase inhibitors with regards to weight loss?
Prevent lipids being hydrolysed by lipases, would ensure the triacylglycerols would remain in the intestinal lumen and not absorbed in the GI tract
What is the purpose of Orlistat?
It reduces calorific intake from foodstuffs by causing the malabsorption of lipids from the GI tract.
How does Orlistat function?
It inhibits lipase enzymes that metabolise triglycerols (TAGs); preventing hydrolysis of TAGs and thus reducing liberation of free fatty acids and monoglycerols, reducing absorption of these energy-rich metabolites, and the TAGs pass out in the faeces.
Is inhibition of lipases by Orlistat reversible or irreversible?
irreversible
Explain how inhibition of lipases by Orlistat is irreversible
Formation of a covalent bond with the serine residues in the active site of gastric and pancreatic lipases. It is highly specific for these enzymes. They are termed suicide inhibitors (or mechanism-based inhibitors) as the drug is effectively used up in the reaction through the irreversible covalent binding to the target.
Name two benefits that absorption of the Orlistat into the systemic circulation is negligible?
i) The action of the drug is required in the GI tract, and therefore absorption would reduce the concentration at the required location.
ii) If absorbed, the drug might act as an inhibitor for other enzymes that operate by the same mechanism (in this case serine hydrolases)
What are anorectic agents?
Substances that reduce appetite, typically reducing consumption, caloric intake and leading to weight loss.
What is rimonabant?
CB1 inverse agonists: demonstrating appetite suppression and commensurate weight loss
Describe the cannabinoid receptor
G-protein coupled receptor that is negatively coupled to adenylate cyclase i.e. it decreases the activity of this enzyme.
Activation of the cannabinoid receptor would cause what change within the cell?
Lead to decreased cellular activity within that cell due to decreased adenylate cyclase activity – a classical depressant effect.
What are the endogenous agonists for the cannabinoid receptor?
Anandamide
- 9-THC (and other cannabinoids) are also agonists for this receptor (albeit less potent)
What side effects would you expect to see with rimonabant, which is a inverse agonist for the CB1 receptor
Depressive effects
suicide and depression
as rimonabant also affects adenylate cyclase activity with concomitant depressant effects
What is taratabant?
Anti-obesity drug based on targeting the CB1 receptor
What is Epidiolex?
Treatment of seizures associated with epilepsy
What does Ghrelin do?
A hormone that stimulates hunger and promotes formation of adipose fat; it is mainly produced by the stomach and small intestine
What is hyperplasia?
An increase in the number of cells (e.g. resulting from cell proliferation) that increases the amount of organic tissue / enlarges the parent tissue
What is hypertrophy?
An increase in size (e.g. of a cell)
What is Leptin?
An adipokine that influences energy balance and satiety/hunger
What is an orexigenic?
An agent that simulates appetite
What is proton-motive force (PMF)
The energy that used to create a chemiosmotic gradient of protons across a membrane
What is thermogenesis?
Production of heat by biological processes such as exercise
What does satiation mean?
The feeling that occurs during an eating episode and reduces the impulse to consume more.
What is satiety?
The feeling of being sated or sufficiently full of food that starts after a meal that prevents further food being consumed, and before feelings of hunger return.
What is a suicide inhibitor?
A drug that covalently binds to a target and inactivates it. Also known as mechanism-based inhibitors.
