Obesity Flashcards
How does obesity predispose to insulin resistance and dyslipidaemia?
Inflammation increases insulin resistance, especially with high FFA
High free fatty acids from visceral fat reach liver and stimulate heptatocytes to synthesise VLDL
VLDL exchanges blood HDL via cholesteryl ester transfer protein
Adipose tissue synthesises TNF-α and IL-6, promoting inflammation and atherogenesis
How is obesity-associated insulin resistance characterised?
Low glade inflammation. Affected adipocyte function and macrophage infiltration of adipose tissue
What is adipose tissue?
Endocrine organ and fat store that secretes signals/hormones
Why is there an acute rise in inflammatory mediators after a meal?
Food is a foreign body which may have potential harm. IL-6 increases
Why is there a larger inflammatory response in obese people after eating?
When adipocytes become full, they leak fats
Macrophages absorb fat as they do this to detect bacterial cell walls. This triggers cytokine secretion e.g TNFα, increasing free fatty acid release from adipocytes, ROS and atherosclerosis risk
What is leptin?
Adipokine which reduces appetite
Increases fatty acid oxidation
Increases insulin sensitivity
Increases energy expenditure
Increased adipose tissue, less fat accumulation
Pro-inflammatory, so increases atherosclerosis risk
Increases BM1
Stimulates thermogenesis in brown adipose tissue via mitochondrial uncoupling
What are some causes of obesity?
Taking in more calories than the body uses
Genes related to appetite regulation, metabolic control and physical activity
70% genetic
40% related to food intake
Explain the carbohydate-insulin model
Obesity isn’t just determined by energy intake vs energy expenditure
Glycaemic load (total carb X glycaemic index)
Lower birth weight- more likely to be obese
Considers form of energy
High glycaemic index - higher blood sugar than foods with same calorific value, insulin processes them into fat
What is the FTO gene
Associated with BM1
α-ketoglutarae-dependent dioxygenase which demethylates mRNA
Increases obesity risk 20%
Stimulates precursor adipose cells to develop white adipose tissue, rather than beige or brown
What can FTO deficiency lead to?
Protection against obesity
Loss of function leads to severe developmental issues
Brown adipocytes made instead
18% heritable variance in gene expression due to copy numbers
Mitochondrial thermogenesis
Why is instance of obesity 50% in african amrican females compared to the average of 36%?
More PARK2 copies alter nerve signals involved with appetite
What influence does the microbiome have on obesity?
Microbiome that extracts more energy from food in obesity
Antibiotics in children may increase risk of obesity
Faecal transplants between mice affect obesity
How does obesity affect the infolded protein response?
Chronic high calorific intake, causing high circulating FFA messes up the ER, causing ER stress and UPR
Long term UPR leads to Range of inflammatory signals causing insensitivity to insulin signalling
What signs is obesity linked to?
Plasma lipids
Glucose
Blood pressure
Inflammation
How does semaglutide work?
Gluagon-like peptide-1 receptor agonist on β-cells, gastric mucosa, kidneys, heart and hypothalamus
Stimulates insulin release and secretion when hyperglycemic
Inhibits glucagon release, slows gastric emptying, reduces food intake
What is the half life of GLP-1
1-2 minutes as DPP-4 degrades it
Where does GLP-1 act?
Stomach (gastric emptying)
Pancreas (increase insulin, decrease glucagon)
Brain (decrease appetite)
How does liraglutide act?
Gluagon-like peptide-1 receptor agonist
Binds albumin in serum, slowing half life to 11-15 hours
Induces weight loss by reducing energy intake by 16% (lab meal paradigm)
How does semaglutide act?
Gluagon-like peptide-1 receptor agonist
Used as a diabetes treatment as it promotes insulin secretion from β-cells in pancreas and decreases glucagon secretion
Reduces energy intake 35% (lab meal paradigm)
What is the energy-balance model?
Obesity is caused by overconsumption o energy-dense processed food and sedentary lifestyle
Considers all calories are metabolically alike
Explain the carbohydrate-insulin model
Increasing fat deposition, resulting from hormonal responses to high glycaemic load diet drives positive energy balance
Insulin increases fat deposition
Considers insulin action in the postpranial period and only in adipose tissue
Considers substrate partitioning and fat deposition by insulin action
How can energy balance and carbohydrate-insulin models be put together
Hardwired hedonic preferences for seetness may drive sugary foods to be eaten (EBM) which affects substrate partitioning through calorie independent mechanisms (CIM)
What is weagovy?
GLP-1 receptor agonist
Induces satiety,slows gastric emptying and insulin production
What monogenic traits are there for obesity?
Melanocortin 4 receptor (MC4R)
Brain derived neurotrophic factor (BDNF)
How does leptin do?
Increases brown adipose tissue thermogenesis due to UCP1 disconnecting oxidation from ATP production by promoting proton leakage across the mitochondrial membrane
