Obesity Flashcards
What does cachectic mean?
Similar to anorexic, where there is loss of fat/ muscle
How much metabolisable energy does 1g carbohydrates or protein give out?
16.8kJ around 4kcal
How much metabolisable energy does 1g of fat give out?
37.8kJ around 9kcal
How much metabolisable energy does 1g of alcohol give out?
29.4kJ around 7kcal
Where is metabolisable energy lost?
Heat loss (50%)
Digestion and absorption (5-10%)
ATP
What is another name for fat tissue?
Adipose tissue
What is the most important neural factor in controlling body weight?
Hypothalamus
What are the main effects of leptin?
Sensor of body fat
Reduces food intake
Expressed in fat cells
Plasma conc proportional to BMI
What is the synthesis of leptin increased by?
Glucocorticoids
Insulin
Oestrogens
What is the synthesis of leptin decreased by?
B2 adrenergic agonists
Name the place where the hormones are made which are released when lectin conc changes:
Arcuate nucleus (ARC) in hypothalamus
Name the hormones which are released when leptin decreases and why?
Orexigenic pathway
Neuropeptide Y (NPY) and Agouti-related peptide (AGRP)
Increased food intake and decrease energy expenditure
Name the hormones which are released when leptin increases and why?
Anorexigenic pathway
Pro- opiomelanocortin (POMC) and a-melanocyte-stimulating hormone (a-MSH)
Decreased food intake and increased energy expenditure
What is the basic mutations for leptin and say how they are overcome?
Mutation in leptin- give leptin
Mutation in leptin receptor so leptin can’t enter cells- can’t give leptin for this
What is the correlation between leptin and obesity?
Obesity is associated with HIGH levels of leptin as higher BMI, higher adipose so increase in leptin
What is the consequence of high levels of leptin in obesity?
Leptin resistance (due to more leptin)
Defect in synthesis
Carriage in circulation
Transport into CNS
Defects in leptin receptors
Which genetic factors are responsible for more energy intake?
FTO
TMEM-18
MC4-R
Leptin
Name two peptide hormones that promote hunger and how do they work?
Ghrelin and leptin
Secreted in wall of SI
Bind to axon receptors on vehicle afferent fibres on hypothalamus and modulate the release of other neurotransmitters to have an impact on eating behaviour
How does Ghrelin affect obese individuals?
Ghrelin promotes hunger, usually after eating the levels decrease but not in obese individuals
What factors are responsible for our energy expenditure?
Basal Metabolic Rate, BMR, (main one)
Physical activity (20-40%)
Thermogenesis
What is BMR?
Amount of energy expended by the body to maintain basic physiological functions over a 24 hour period
How is BMR calculated?
Subject to lying at physical and mental rest and warm at least 12 hours after last meal
Mask over face using oxygen consumption
What does BMR vary with?
-Body weight
-Body composition (decreased fat, increased protein so increased BMR)
-Age (18-25 BMR peaks then decreases)
-Gender
-Genetic factors
-Other factors e.g smoking increases BMR
What is meal induced thermogenesis?
Increase in metabolic rate following food consumptions
Occurs over 5 hours
Approx 10% of caloric content of food
How is the sympathetic nervous system involved in energy expenditure?
CV, skeletal muscle, thermogenesis
Brown fat, extensive sympathetic innervation
B3 adrenoreceptors, thermogenesis and lipolysis, expression decreases with obesity
What does the hypothalamus innervate to regulate thermogenesis?
Neurotransmitters-> pituitary and autonomic NS which regulates thermogenesis
How is brown fat involved in weight loss?
Brown fat has increased mitochondria compared to white fat, so remarkable heat generators (which burn calories)
This is because they have mitochondria uncoupling proteins (UCP), they uncouple oxidative phosphorylation so that mitochondria release energy into heat rather than ATP
How can genetic factors cause obesity and at which genes are they?
Inheritability 30-40%
Fat distribution, resting metabolic rate, energy expenditure after overeating, lipoprotein lipase activity and basal rates of lipolysis
UCP-2, MC4R (Melanocortin 4 receptor)
Describe single gene disorders linked to obesity:
Around 200 associated
Not leptin or leptin receptor
Links to B3 adrenoreceptors and glucocorticoid
What is a positive energy balance?
More taken in rather than expenditure, gain in energy store, so obesity
What is a negative energy balance?
Less taken in, more expenditure, loss in energy store, so under nutrition
What BMI is overweight and obese?
25 or above = overweight
30 or above is obese
What is a healthy BMI?
Anything 18.5-24.9
What are the main major complications of being overweight/ obese?
Type 2 diabetes
Sleep apnea
Cardiovascular issues
Gall bladder disease
Breathlessness
What is the main way to lose weight?
Eating less and increasing exercise
Reduce energy intake by 600kcal a day
150 mins of moderate activity a week
What are three ways to target obesity via drugs?
Appetite suppression- CNS acting
Decreased absorption- Orlistat, fibre supplements
Increased metabolism- activation of brown adipose tissue on B3 receptors, activates UCP1 gene, as B3 expression decreased in obesity
Name and describe the composition of fats:
Triglycerides= esters of fatty acids and glycerol
Fatty acids- saturated and unsaturated
Describe saturated fatty acids:
Single bonds (bad)- animal fats, butter
Describe unsaturated fatty acids:
Polyunsaturated e.g omega 3 (fish) and 6 (sunflower oil)
Monounsaturated e.g omega 9 (olive oil)
How are fats absorbed?
Triglycerides are too large to be absorbed
They are solubilised by formation of micelles with the aid of detergent such as cholesterol and bile acids
Secreted pancreatic lipase acts at the water/ micelle interface to hydrolyse the ester linkages to give free fatty acids are absorbed by the intestine
How does lipase work?
Enzyme contains an active site sereine residue
Sereine is activated by deprotonation by neighbouring residues, it then attacks glyceride and cleaves the ester bond
A covalent acyl enzyme intermediate is formed which is hydrolysed by water to release a fatty acid
How does lipstatin work?
Decrease in fat intake by inhibition of pancreatic lipase
The ester is attacked by the active site sereine residue in pancreatic lipase with the natural substrate, the acyl sereine intermediate would undergo hydrolysis to release the fatty acid, with Lipstatin, the acyl serine intermediate is stable and hydrolysis requires 24 hours- irreversible inhibitor
This prevents breakdown of tricylcerides and so decrease in absorption
Why is lipstatin changed to tetrahydrolipstain (Orlistat)?
The alkanes in lipstatin make the molecule prone to oxidation upon storage and in vivo metabolism
Hydrogenation saturates the molecule and removes this problem
Why does it not matter that orlistat has a low bioavailability?
Reduces systemic side effects
What is the dosing of Orlistat OTC AND POM?
OTC: 60mg
POM: 120mg TDS before meals- 30% of dietary fat not absorbed
What are the conditions for taking Orlistat?
For pts with BMI over 30 and caloric reduction or with pts with BMI over 28 with other risk factors
Given for free to pts who have lost 2.5kg from dieting month prior
Orlistat should be stopped after 12 weeks if patient hasn’t lost atleast 5% of body weight
What are the side effects of Orlistat?
Due to fat not being absorbed its released into the faeces, so significant effect on GI, steatorrhea, wind and faecal incontinence
Aversion therapy, the more food eaten the more side effects
What are the interactions of Orlistat?
The absorption of the contraceptive pill and ciclosporin may be reduced
How is melanocortin involved in obesity?
Obesity stimulates the melanocortin pathway leading to increase in blood pressure and heart rate and catabolic activity
Describe the signalling cascade from serotonin to melanocortin:
Serotonin (5-HT) binds to the 5-HT2c receptor, a GPCR in the pituitary gland
This stimulates production of Pro-opiomelanocortin (POMC)
POMC is cleaved to give alpha-melanocyte stimulating hormone (a-MSH)
There a-MSH binds to its receptor, a GPCR
Mutations in the melanocortin receptor 4 (MC4-R) are the most common genetic predisposition to obesity
Describe Buprion/ naltrexone as a weight loss medication:
Buprion- a norepinephrine dopamine reuptake inhibitor
Naltrexone- opioid receptor antagonist
Marketed as sustained release form (Contrave)
Available by private prescription, too expensive on NHS
Describe Setmelanotide as a weight loss medication:
Not orally active
Synthetic MC4R receptor agonist
Increases satiety
Increases energy expenditure
Increases growth
Name 2 diabetes drugs which are also used for obesity and MoA:
Liraglutide
Semaglutide
GLP1 agonist
