Immunity and metabolism Flashcards
How are obesity and type 2 diabetes linked?
Obesity causes chronic low grade inflammation which along with activation of the immune system is involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes
A number of experimental and clinical data have clearly established that adipose tissue, liver, muscle and pancreas are sites of inflammation in presence of obesity and T2D
What are the different types of adipose tissue?
White adipose tissue
- Contain single large lipid droplet, few mitochondria
- Secretes adipose derived hormones that regulate insulin sensitivity and satiety
- Stores excess energy as triglycerides, releases fatty acids during fasting periods
- Usually found in the abdominal regions
- Energy reservoir –> can store large quantity
Brown adipose tissue
- Contain small lipid droplets, rich in mitochondria
- Densely vascularised and innervated by sympathetic nerve endings –> more blood vessels
- Expression on uncoupling protein 1
- Dissipates chemical energy (mainly from fatty acids) to generate heat
- Amount determined by genetics and some other factors, hard to be modified
- Localised in specific parts of the body like lungs and neck area
Why is the fact that brown adipose tissue has more mitochondria and more blood vessels important/ beneficial?
Having a close blood supply provides the mitochondria with nutrients and oxygen to work affectively
Fatty acids can only be used in mitochondria –> only can be oxidised in mitochondria and for this, it require oxygen.
Without this oxygen supply there is a limited capacity to produce ATP.
This constant oxidation of free fatty acids is a key factor in regulating body temperature and keeping it around 37’c/ in a healthy range
What is the link between obesity and immunity?
Obesity is characterised by the accumulation of diverse immune cells in the adipose tissue
Adipose tissue macrophages accumulate in both the subcutaneous and visceral expanding fat depot, even though macrophage infiltration appears to be more prominent in the latter
How does obesity affect macrophages?
Macrophages are tissue resident cells which when in the adipose tissue are known as adipose tissue macrophages (ATM). There presence is not a problem in normal physiological conditions.
When adipose tissue volume increases from a positive energy balance.
The expansion of adipose tissue occurs from adipocyte hypertrophy –> reaches a point where adipocytes cannot grow any more, which causes hyperplasia to occur –> increasing number of adipocytes in AT.
Obesity, hypertrophy and hyperplasia increases the infiltration of macrophages in the AT.
changes the phenotypes of macrophages from M2 to M1 which contributes to creating a more inflammatory environment. This occurs when the expansion of the AT begins to damage the adipocytes, which causes macrophage activation.
Why is there not the same ability to store glycogen as with fat?
Glycogen requires 3 grams of water for each gram of glycogen to be stored.
Don’t have the same ability to store glycogen as fat.
Fat doesn’t require water
Also there is a high ability to expand the adipose tissue, especially in the abdominal cavity which increases the capacity to store fat
What are the two phenotypes of macrophages?
M1
- Pro-inflammatory
- Release large quantities of free radicals
- Inflammatory cytokines –> IL-6, TNFa, IL-12
- Useful acutely in response to damage to help with healing and destroy any pathogens or abnormal cells
M2
- Pro-resolving
- Non-activated macrophages –> doesn’t mean not functional –> in a semi inactive role
- Release small quantities of anti-inflammatory cytokines which is helpful in cell signalling between organs –> IL-10, TGF-B
- The phenotype which is found in healthy individuals
- When become active they can change and become M1
- Also increase angiogenesis
- Low microbicidal activity
What can explain the higher infiltration of macrophages in high levels of adipose tissue?
Hypertrophy and hyperplasia of adipocytes increasing amount of ATM
Damage of adipocytes from over expansion causing activation of macrophages into M1
Release of the chemokine Monocyte Chemoattractant Protein-1 (MCP1) which is secreted by hypertrophic adipocytes, this is a key factor in why the number of macrophages increases in increasing AT levels.
This then causes an increased inflammatory response in the AT due to the conversion of macrophages from M2 to M1 which promotes inflammation.
What is the mechanism of macrophages?
M2
- Aerobic respiration with pyruvate being oxidised in the mitochondria to produce ATP
- Anaerobic can occur but less than M1
M1
- Metabolic pathway usually uses pyruvate in the anaerobic pathway which produces lactate and hydrogen
- More lactate produced than in M2
- Hydrogen can be used is ETC
- Chronically with obesity, mitochondria can become dysfunctional where there is a lower ability to reduce hydrogen
- Can create a hypoxic environment
What happens with chronic AT expansion?
Adipocyte hypertrophy and hyperplasia –> adipocyte damage and MCP1 secretion –> M2 activate to M1 –> release pro-inflammatory cytokines
M1 produces more lactate and hydrogen as generally respires anaerobically. Obesity is linked to mitochondrial dysfunction due to the inflammatory response from increased inflammatory cytokine production causing oxidative stress. This mitochondrial dysfunction means there is a lower ability for aerobic respiration so less hydrogen is used in the ETC and is not reduced. This causes a build up of hydrogen ions in the body.
The expansion of AT occurs quicker than the formation of new blood vessels. The more adipocytes the higher energy demands. More energy is needed to feed these bigger cells however there is not the same ability to utilise oxygen due to the decrease in angiogenesis.
Anaerobic glycolysis occurs to help maintain energy requirements –> more lactate and hydrogen causes a reduction in intracellular pH which in turn affect mitochondria. Acidification of cells can lead to mitochondrial dysfunction and oxidative stress. This mitochondrial dysfunction also causes a decrease in fat metabolism
Creates a hypoxic environment where there is not enough oxygen and adipocytes rely on anaerobic glycolysis.
AT damage can cause an infiltration of T killer cells (CD8) which translocate to the AT to try and get rid of the damaged adipocytes. The more damage in the AT, the higher levels of T killer cells. T Killer cells can release more cytokines which can lead to more metabolic disturbance/ insulin resistance.
There is an imbalance between T killer cells and T regulatory cells which can impair ability to reverse inflammatory response.
Hypertrophy can provoke adipocyte necrosis and release of their cellular contents into the extracellular space triggering an inflammatory response. Particular some of the moribund or dead adipocytes become surrounded by macrophages to form crown like strcutres observed in expanding tissue.
How can expansion of AT cause problems in other parts of the body?
The main physiological response to increasing AT is insulin resistance.
AT damage can cause an infiltration of T killer cells (CD8) which translocate to the AT to try and get rid of the damaged adipocytes. The more damage in the AT, the higher levels of T killer cells. T Killer cells can release more cytokines which can lead to more metabolic disturbance/ insulin resistance.
There is an imbalance between T killer cells and T regulatory cells which can impair ability to reverse inflammatory response.
What can link all the mechanisms surrounding AT expansion and insulin resistance?
The increase in the adipocyte and immune cells release of cytokines can down-regulate proteins participating in the insulin signalling cascade.
When insulin binds to receptors on the cell membrane of liver cells, triggering a cascade of reactions in the cell. At least 10 different proteins are activated, these proteins have the role of translocation of GLUT-4 to the cell membrane to allow glucose entry.
If these intracellular proteins are not very functional, AKT is often affected by cytokines. AKT is essential for glucose transport translocation. If this protein is down-regulated this can affect the uptake of glucose into cells causing blood glucose levels to remain high.
ALSO
When large quantities of energy is being stored as fat, a common response of the AT is to try and get rid of the FFA and releasing them to the circulation. There is a rapid exchange/turnover of FFA between AT and the liver (has a large ability to store fat). The liver forms ceramide (naturally), with excess FFA there can be an excess of ceramide production. The liver tries to get rid of the ceramide by packing it in lipoproteins and releasing to other organs.
This is another mechanism that can explain why the accumulation of fat and low grade inflammation can trigger IR.
The accumulation of ceramide in the liver can induce mitochondrial dysfunction and increase oxidative stress. If mitochondrial function is impaired it can compromise the ability to oxidise fatty acids.
The ceramide can be packed into very low density lipoproteins (VLDL) which goes into the bloodstream and targets the muscle. Causes accumulation of cermide into the muscle which can also impair ability to take glucose into the muscle tissue.
The large accumulation of ceramide in the muscle and liver has been related to the up-regulation of genes that express inflammatory cytokines and MCP1 (linked to M2 activation and pro-inflammatory response)
The over expression of these peptides can down-regulate AKT which plays a key role in the insulin cascade signalling meaning less translocation of GLUT4 to cell membrane for glucose uptake.
How does ceramide production play a role in insulin resistance?
When large quantities of energy is being stored as fat, a common response of the AT is to try and get rid of the FFA and releasing them to the circulation. There is a rapid exchange/turnover of FFA between AT and the liver (has a large ability to store fat). The liver forms ceramide (naturally), with excess FFA there can be an excess of ceramide production. The liver tries to get rid of the ceramide by packing it in lipoproteins and releasing to other organs.
This is another mechanism that can explain why the accumulation of fat and low grade inflammation can trigger IR.
The accumulation of ceramide in the liver can induce mitochondrial dysfunction and increase oxidative stress. If mitochondrial function is impaired it can compromise the ability to oxidise fatty acids.
The ceramide can be packed into very low density lipoproteins (VLDL) which goes into the bloodstream and targets the muscle. Causes accumulation of cermide into the muscle which can also impair ability to take glucose into the muscle tissue.
The large accumulation of ceramide in the muscle and liver has been related to the up-regulation of genes that express inflammatory cytokines and MCP1 (linked to M2 activation and pro-inflammatory response)
The over expression of these peptides can down-regulate AKT which plays a key role in the insulin cascade signalling meaning less translocation of GLUT4 to cell membrane for glucose uptake.
In obesity the activity of Paneth cells is impaired which reduces ability to produce antimicrobial peptides and can create an opportunity for pathogenic bacteria to grow.
With compromised Paneth cells and lower numbers of competitors for pathogenic bacteria, can be a factor in why there is lower species diversity of bacteria.
The bacteria most affected by this are commensal bacteria or bacteria that produce SCFA from fibre. The production of SCFA in the gut is important in enhancing insulin sensitivity, especially in the liver.
How can inflammation affect the gut microbiome and overall immunity?
Obese individuals have less diversity of bacteria in the gut.
The lower the diversity the higher chance of pathogenic bacteria to colonise some parts of the gut.
In obesity the activity of Paneth cells is impaired which reduces ability to produce antimicrobial peptides and can create an opportunity for pathogenic bacteria to grow.
With compromised Paneth cells and lower numbers of competitors for pathogenic bacteria, can be a factor in why there is lower species diversity of bacteria.
The bacteria most affected by this are commensal bacteria or bacteria that produce SCFA from fibre. The production of SCFA in the gut is important in enhancing insulin sensitivity, especially in the liver. This is heightened further with a low fibre diet.
What is the best way to manage chronic inflammation?
In obesity, weight loss induced by surgery or diet and exercise.
Reduce accumulation of energy in form of fat in the ATP –> best way to do this is through having a negative energy balance.
This fat reduction will reduce the number of ATM in parallel to the decreased expression of pro-inflammatory markers (IL-6, CRP) in both the AT and plasma.
This is shown after bariatric surgery, where after a large reduction in fat, there is a significant reduction in inflammatory markers.
