Lecture 28; immunometabolism Flashcards
What was the initial discovery of immunometabolism? (involves TNFa)
~ 20 years ago, TNF-a administration shown to lead to hyperglycemia (cant take up blood glucose)
then
TNF-a elevated in obese rodents (Adipose Tissue Macrophages), neutralization of TNF-a improved insulin resistance and TNF-a-deficient mice had improved insulin sensitivity during diet-induced obesity
I.e overnutrition does this,
In obese mice what is thought to be responsible for the hight TNFa?
Nutrient overload activates inflammation in insulin-target tissues (e.g. adipose tissue, liver, skeletal muscle, pancreas, hypothalamus)
What basic factors does metabolism and immunity share?
- Sensors transduce stimuli into downstream mediators that activate effector responses to eliminate stimulus-return to homeostasis
- Metabolism and immune response organised in the same way
- A shared modular architecture
It is believed that overnutrition can alter the immune cell representation in adipose tissue and thus the inflammatory profile to a proinflam response
Describe the immune profile of adipose tissue in a lean individual;
- Release of Il4,13 (antiinflam) by eosinophils
- Th2 and Tregs release IL10
Combination of these cytokines maintains an entry level macrophage state. (anti-inflam state, surveillance phenotype)
Describe the immune profile of adipose tissue in a obese individual;
Obese state, immune cells recruited, recruited monocytes polarized to highly pro-inflammatory M1 state/insulin resistance
• Cytokines/chemokines stimulate inflammation in other tissues in an endocrine manner
Th1, cd4, cd 8 now present
adipokines promote M1 state of macrophages as well as pro-inflam state (promotes insulin resistance, TNFa)
Describe the shift in adipose immune cells in an obese individual;
Increased;
- M1
- Mast cells
- B2
- CD8
- IFNg Th1
= Proinflam response
Decreased
- M2
- Eosinophils
- Treg
= decreased anti-inflam profile
What diseases can result from the chronic low grade inflammation on an obese individual?
- Dementia (CNS inflam)
- Immune dysfunction
- Atherosclerosis (lipid uptake my macros)
- Diabetes
- Pancreatitis
- Athritis
- insulin resistance
- Gout
- Cancer
Describe the relationship between Infection, immunity and insulin resistance;
• Bacterial infection activates innate immune cells-release of pro- inflammatory cytokines that mediates IR in metabolic tissues • IR in liver-increased gluconeogenesis • IR in muscle-decreased glucose disposal and increased breakdown of glycogen • Elevated glucose can fuel immune cell activation • IR in adipose tissue-increased break down of lipids and decreased lipogenesis • Elevated FFAs can support immune cell metabolic demands • Nutrients diverted to support immunity
What influences immune cell functional activity?
The mode of fuel that they use i.e FFA or glucose.
How does IR occur?
- Stimulation of pro-inflammatory signalling pathways negatively regulates insulin signaling leading to insulin resistance
- TNF-a can stimulate serine kinases (IKK, JNK, S6 kinase) that leads to serine phosphorylation of insulin receptor substrate-1
What are three pathways that can drive inflammation that can lead to IR?
- Saturated fatty acids can signal through TLRs to regulate pro- inflammatory gene expression
- Inflammasome activation also contributes to pro-inflammatory signalling
- Omega-3 fatty acids and IL-10 anti- inflammatory signalling, i.e. decrease IR
Describe the M2 macrophage signalling in adipocytes in a lean state;
(signal mechanisms between the two cells)
- Eosinophils can release IL4,13 that act through their receptors i.e STAT6 which drives anti-inflammatory pathways
- m2 then can produce Il10 (anti) which can act on adipocytes to enhance its insulin sensitivity.
- Alternatively adiponectin or omega FA 3, can act via receptors and AMPK to inhibit pro-inflam signals. (fortifying anti-inflam signalling)
Describe the M1 macrophage signalling in adipocytes in a obese state;
(signal mechanisms between the two cells)
IN the adipocyte;
- Increased adipolysis, these FFA can act via TLR on M1 and drive a pro-inflam state (TNFa)
- TNFa acts on adipocyte and up regulates more proinflam genes. (becomes a cycle perpetuating one another)
- M1 cells release CD5-like antigen, taken up by adipocyte by CD36-mediated endocytosis, promotes break down of lipids
• SFAs perpetuate M1 activation and adipocyte pro-inflammatory phenotype
Both adipocytes and M1s recruit monocytes = skewed M1 production
Whats the evidence of autoantibody production in adipose tissue of an obese individual?
- When adipocytes become engorged in an obese individual, some undergo necrosis.
- These are phagocytosed and derived self antigen can be presented to TH1 cells.
- Clonal expansion of th1
- This can lead to activation of B cells producing autoantibodies
which can lead to type two hypersensitivity reaction
What is oxidative phosphorylation?
OXPHOS-oxidation of nutrients in the mitochondria to produce energy (TCA cycle and electron transport chain)
