Over Nutrition Flashcards
what are the 3 major consequences of over nutrition?
Increase in risk of:
• coronary heart disease
• Type 2 diabetes
• Non-alcoholic fatty liver disease (NAFLD)
what is an early lesion of atherosclerosis?
fatty streak (precursor lesion before plaque)
Accumulation of lipid in vessel wall
what is a late lesion of atherosclerosis?
atherosclerotic plaque
what is an early atherosclerotic lesion made up of?
Cells, mainly macrophages, containing cholesterol ester. Cells contain the Cholesterol ester (coupled with fatty acids)
Few smooth muscle cells
what is a late atherosclerotic lesion made up of?
Central lipid core (still cholesterol) and fibrous cap and myeloproliferative tissue (muscle cells that are proliferating) consisting of smooth muscle cells and extracellular matrix
what is the first possible mechanism of the formation of atherosclerosis?
LDL & macrophages accumulate in vessel wall -> Macrophages produce ROS* -> ROS attack LDL oxidised LDL -> Oxidised LDL taken up by macrophages** (uptake is via scavenger receptors & is uncontrolled)
- Macrophages can be triggered to go into respiratory burst and realise ROS
- oxidised LDL cant be taken up by usually mechanism or deliver cholesterol as usual – taken in by macrophages (scavenger receptor).
what is the second possible mechanism of the formation of atherosclerosis?
Lipid laden macrophages = foam cells -> Fatty streak -> Platelets aggregate & are activated Smooth muscle cells proliferate Collagen is synthesised Foam cells die releasing lipid -> Atherosclerotic plaque
what is the initiating event of atherosclerosis?
- Various theories including
- Injury to vessel wall (endothelial injury)
- Endothelial dysfunction
- Excessive entry of LDL into vessel wall - All three mechanisms could trigger recruitment of macrophages
- Endothelial injury and dysfunction could be due to inflammation whilst later associated with raised circulating LDL/cholesterol
what is the pathology of NAFLD?
Accumulation of liver (triglycerol) In liver
Can progress to non-alcoholic steatohepatitis (NASH) and cirrhosis
Lesions similar if not identical to those seen in alcohol abusers
what is the pathogenesis of type 2 diabetes?
Involves insufficiency of insulin secretion to maintain normal homeostasis
Typically results from insulin resistance
what is the mechanism of insulin resistance?
Tissues fail to respond adequately to insulin
->
Blood glucose concentration tends to increase
->
Further insulin secretion
->
Blood glucose concentration normalised
what is the mechanism of type 2 diabetes?
Tissues fail to respond adequately to insulin
->
Blood glucose concentration tends to increase
->
Pancreas unable to mount adequate response Due to extent of insulin resistance &/or secondary B Cell failure
->
Blood glucose concentration continues to increase
what is the definition of metabolic syndrome?
Clustering of cardiometabolic risk factors that are likely to be linked to insulin resistance
what are the risk factors of metabolic syndrome?
Abdominal obesity
Hyperglycaemia
Dyslipidaemia
Increased Blood Pressure
people affected by metabolic syndrome are at increased long term risk of…?
cardiovascular disease, type 2 diabetes mellitus & NAFLD
IDF consensus values for metabolic syndrome
CENTRAL OBESITY
Central Obesity
Waist
≥ 94 cm (male)
≥ 80 cm (female)
IDF consensus values for metabolic syndrome
ANY 2 OF THE FOLLOWING
Serum Triacylglycerol*
≥ 1.7 mM
Serum HDL-c
< 1.03 mM (male)
< 1.29 mM (female)
Blood Pressure (BP) Or be on treatment for thIs
≥ 130/85 mmHg
Fasting plasma glucose Or be diagnosed with type 2 diabetes mellitus
≥ 5.6 mM
what is the prevalence of metabolic syndrome?
- Adults 20+
- Increases with age – 50% 60+
- More common in men
- Increasing as obesity increases and population ages
what can metabolic syndrome be used to predict?
CHD risk
Framingham risk score -> ability to identify risk where traditional approaches to assessing risk based on age, sex, smoking, total cholesterol levels give low score
what are the characteristics of adipose tissue?
Secretes range of endocrine, paracrine & autocrine substances
Some exclusive to adipose tissue, e.g. leptin & adiponectin
Others generic, e.g. cytokines such as tumour necrosis factorα (TNFα)
Effects include modulation of storage & use of fuel, promotion of inflammation, & alteration of vascular tone (vasodilatation)
Latter important as when tissue active, blood flow needs to
what is leptin and what does it do?
Overall signals “enough energy for living”
Anorexigenic
Decreases intracellular lipids
Improves insulin sensitivity by limiting food intake
Inhibits glucocorticoids & enhances action of thyroid hormones, sex steroids & growth hormone
what is adiponectin and what does it do?
Self-regulating signal for adipose tissue capacity
Modifies metabolism withdrawal of free fatty acids from circulation through incorporation into fat deposits & promotion of fatty acid oxidation in skeletal muscle
Promotes glucose oxidation & decreases hepatic glucose production -> increase in insulin sensitivity
Suppresses inflammation
decrease in circulating concentration when adipose tissue replenished, in obesity, diabetes mellitus &/or insulin resistance
what is resistin and what does it do?
Associated with inflammatory conditions,
e.g. obesity & insulin resistance
Decreases insulin sensitivity in adipocytes, hepatocytes & smooth muscle cells
Production increased by pro-inflammatory cytokines, e.g. tumour necrosis factorα (TNFα)
what are pro-inflammatory cytokines and what do they do?
Includes interleukin 6 (IL-6) & tumour necrosis factorα (TNFα)
Produced by adipocytes & infiltrating immune cells, e.g. macrophages
Both antagonise adiponectin
Circulating IL-6 levels increased in obesity & insulin resistant states
IL-6 promotes insulin resistance
why is visceral fat different to adipose tissue?
Visceral fat more active in terms of accepting & releasing fatty acids
Visceral fat in privileged situation for receiving fat input & releases free fatty acids directly to liver
While subcutaneous fat able to store energy, visceral fat able to buffer fat levels effectively
When subcutaneous depots full, visceral area takes over impaired buffering capacity
what happens when adipose tissue fails?
Permanent switch to releasing fatty acids leading to excess flux to other tissues at all times together with associated reduction in clearance of triacylglycerol carried by VLDL & chylomycrons (lipoproteins)
Liver
Excess FA -> Triacylglycerol -> VLDL etc.
Other tissues
Excess FA suppress glucose use
what are the causes of adipose tissue failure?
Type 1 diabetes mellitus – lack of insulin
Polycystic ovarian syndrome – impaired suppression of fat breakdown & of stimulation of triacylglcyerol uptake by insulin due to abnormalities in other hormone levels
Lipodystrophy - decrease in amount of tissue
Excess demands – obesity
Genetic susceptibility - increase in sensitivity to demand
what is mechanism 1 of adipose tissue failure?
genetics and environment act on adipose tissue
adipose tissue exceeds capacity
overloaded tissue and equilibrium point moved
what is mechanism 2 of adipose tissue failure?
overloaded tissue
chronic inflammation
endothelial dysfunction
what is mechanism 3 of adipose tissue failure?
equilibrium point moved
vascular regulation -> hypertension
or
lipid flux to other tissues -> Dyslipidaemia & dysglycaemia
what other factors impact on atherosclerosis?
Inflammation
- decrease in adiponectin (anti-inflammatory)
- increase in pro-inflammatory cytokines, e.g. TNFα, IL-6
Potential for endothelial dysfunction
Potential for ROS production, e.g. via respiratory burst -> oxidative stress
what other factors impact on NAFLD?
Inflammation (as before)
increase in fatty acid (FA) flux to liver
FA arriving at liver faster than can be used by
β-oxidation
Surplus channelled into triacylglycerol synthesis
what other factors impact on insulin resistance?
Likely to result both from changes in signal transduction elements & altered fuel availability
Key factors:
decrease in adiponectin
increase in resistin & IL-6
increase in circulating fatty acids -> suppression of glucose use & promotion of gluconeogenesis
what are the characteristics of lipoproteins?
Transport lipid in blood
Chylomycrons carry dietary lipid (mainly triacylglycerol plus some cholesterol)
VLDL carry lipid away from the liver (mainly triacylglycerol plus some cholesterol)
LDL formed from VLDL by removal of triacylglycerol & carry mainly cholesterol
Approximately 70% circulating cholesterol on LDL level = major determinant of serum cholesterol concentration
HDL carry cholesterol back to liver
