EXAM Lecture 16 Flashcards
Shift towards inflammation in obese adipose tissue (AT)
- increase in T cells
- increased macrophage infiltration into the AT (in response to MCP1 etc) become M1 and decreased M2 = more inflammatory mediators
M1 macrophages produce inflammatory cytokines (MCP1, TNFa, IL6)
- HIGH expression of F4/80, CD11b, CD11c surface markers compared to lean
- express iNOS intracellularly; produce nitric oxide (inflammatory)
- take up some fatty acids (contributes to FFA)
LOSS of anti-inflammatory, immune suppresive, and insulin sensitizing signals in obese AT
- decreased number of M2 macrophages; M2s usually secrete anti inflammatory cytokines (IL10, TGFb) and repair AT
- decreased number and function of Treg; suppressed by leptin (usually secretes anti inflammatory cytokines (IL10))
- decreased production and secretion of adiponectin by adipocytes; usually promotes M2
- decreased production and secretion of IL10 (an anti inflammatory)
Macrophage polarization and dietary fatty acids
- monocytes are recruited by AT from blood by chemotactic signals (MCP1)
- they enter AT and differentiate into M1 or M2
- obese inflammatory AT microenvironment will push monocytes to differentiate into M1 macrophages
- maintaining a high fat diet but supplementing with DHA (n-3 PUFA)
= increased M2 and decreased M1
Saturated fatty acids promote inflammatory mediator production
saturated free fatty acids bind TLR2 or 4 which is stimulated by LPS from microbiota
then it activates two inflammatory transcription factors: NFkB and JNK - leads to increased inflammatory mediator production
this is all happening in M1s, adipocytes, skeletal muscle, liver
N-3 PUFA (DHA and EPA) go through either PPARy dependent or independent mechanisms to inhibit NFkB
N-3 PUFA and anti inflammatory effect
N-3 PUFA utilize a unique surface receptor called GPR120
- activates Barr2 and TAB1 which inhibits downstream signalling steps in other pathways (TBK1 and TAK1), NFkb, and cytokine production
- these inflammatory mediators suppress insulin mediated signalling (phosphorylaton of IRS1)
- activation of PI3k stimulates GLUT4 (restores glucose uptake)
Insulin signalling
Normally:
- insulin binds to insulin receptor
- phosphorylation of IRS1/2
- activation of PI3K
- eventual translocation of GLUT4 to the plasma membrane: allows for blood glucose to be taken up by adipocyte (insulin stimulated glucose uptake)
obesity:
- TNFa and IL6 block IRS1 phosphorylation
- sat FA block IRS1 from interacting with PI3K
result = no translocatioon of GLUT4 to the plasma membrane (no glucose uptake and cell is insulin resistant)
Glucagon like peptide 1 (GLP-1)
improves gluoce homeostasis and reduced insulin resistance
- increasing GLP1 regulates glucose, controls appetite, reduces insulin resistance, etc
Resveratrol and obesity (HF+R)
limits high fat diet induced body weight gain
- decreased accumulation of adipose tissue
increased intestinal epithelial cell expression of GLP1
- improves glucose homeostasis and stimulates pancreas secretion of insulin
increases adipose tissue secretion and blood levels of adiponectin
decreases FFA release from adipocytes
decreases liver lipid accumulation
BUT could never get sufficient amount thru wine/food - need powder supplement
Turmeric and curcumin
the principle polyphenol in turmeric is curcumin
anti inflammatory effects
- reduce the activation of STAT3 transcription factor; decreases IL6 production
- upregulates PPARy activation (inhibits NFkB)
- reduces FFA release from adipocytes (which can be inflammatory via stimulating TLR2/4)
anti diabetic effects in T2D
- reduced fasting blood glucose and increased glucose uptake (improves insulin resistance)
- reduce serum TG and FFA release
- increase blood adiponectin levels
Apples
whole apples are rich in polyphenols - very high in FREE phenolics (more bioavailable):
- quercetin
- catechin
associated with decreased risk of developing T2D, altered gut microbiota, etc
other sources of purified quercitin:
- onions, elderberries
Purified Quercitin effects in obesity
reduced macrophage and adipocyte secretion of chemokines that recruit more macrophages into adipose tissue (MIP1a, MCP1) = fewer M1
reduces inflammatory mediators (TNFa, MCP1)
reduces TLR4 expression at AT; makes adipocytes less responsive to LPS or SFA
reduced NFkB activation
stimulates glucose uptake and activates GLUT4 translocation to cell surface
liver - increases glucose uptake via GLUT2 and increases activity of glyocgen synthase
Cocoa
Cocoa is a rich source of polyphenols
clinical trial showed reduced activation of NFkB (result was lost when mixed with milk)
other studies show reduced serum CRP levels (inflammatory biomarker), improvement in insulin sensitivity, reduced M1 (and resulting cytokines)
cocoa supplementation on high fat diet increases plasma GLP2:
- GLP2 enhances epithelial barrier integrity by increasing expression of claudins, occludins, ZO1
Cocoa diagram
obesity:
- adipokines decreased (IL6, TNFa, leptin)
insulin resistance
- cytokines decreased (IL6, TNFa)
- improved B cell function
- increased GLUT4 translocation
inflammation
- decreased cytokines (IL1/2/4/6, TNFa, MCP1)
- decreased CRP, NO, NFkB
- modulates glut microflora
