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NUTR 3360 > Module 8: Adipose Tissue Role in Metabolic Complications > Flashcards

Module 8: Adipose Tissue Role in Metabolic Complications Flashcards

1
Q

Insulin resistant adipose tissue is associated with (3 answers)

A

-high blood FFA
-low levels adiponectin (insulin-sensitizing adipokine)
-decreased expression of key adipogenic transcription factors (PPARγ, C/EBP, etc)

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2
Q

Blood Markers in Type 2 Diabetes

A

increased blood NEFA and triglyceride levels. also higher bl glu and ins

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3
Q

NEFA in blood bound to

A

albumin

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4
Q

What does NEFA serve as

A

source of energy for liver, muscle, and other organs

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5
Q

4 fates of NEFA in liver

A
  1. Used for energy
  2. Stored as TAG in lipid droplets
  3. Packaged as TAG into VLDL
  4. If glucose levels are low (i.e., during starvation), NEFA are used to make ketone bodies for use by the brain
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6
Q

NEFA and insulin sensitivity

A

strong inverse relationship between blood NEFA levels and insulin sensitivity

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7
Q

NEFA levels during the day

A

Blood NEFA levels are highest in the morning (after an overnight fast), drop strongly after breakfast, and then increase gradually during the day.

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8
Q

Role of insulin on fat uptake in adipose (4)

A
  1. glucoseuptake by promoting GLUT4
    translocation to the plasma membrane.
  2. induces Lipoprotein Lipase (LPL), promotes breakdown of TAGs in lipoproteins to allow for fatty acid uptake.
    3.induces diacylglycerol acyltransferase (DGAT) activity, which is necessary for TAG synthesis and fatstorage.
    4.Insulin inhibits hormone sensitive lipase (HSL) activity, thereby preventing lipolysis.
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9
Q

LPL and fat uptake into adipose tissue relationship

A

-correlated w fat uptake into adipose tissue

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10
Q

Is LPL activity in adipose tissue
regulated by nutritional status?

A

Mice that are fasted have low LPL activity (which limits fat uptake)
food-increase in LPL

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11
Q

HSL-/- mice

A

-larger adipocytes (less lipolysis)
-reduced TAG activity in white adipose tissue, no change in brown

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12
Q

VLDL production/secretion and insulin sensitivity relationship

A

VLDL production & secretion is inversely associated with insulin sensitivity

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13
Q

VLDL production/secretion and obesity relationship

A

Obesity is associated with increased VLDL secretion

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14
Q

What does HSL control

A

adipose tissue lipolysis

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15
Q

Primary adipose tissue depots

A

-subcutaneous
-visceral

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16
Q

Primary role of adipose tissue

A

store excess energy in adipocytes

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17
Q

Hyperplasia

A

increase in cell number

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18
Q

Hyptertrophy

A

increase in cell size

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19
Q

Bariatric surgery cell vol and number change

A

Lower cell volume, no change in number

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20
Q

Lifespan and production of fat cells lean vs obese

A

The average lifespan for an adipocyte is the same in lean and obese individuals, but the production rate of adipocytes is higher in individuals with obesity

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21
Q

changes in size and number of fat cells between depots

A

Adipocyte cell size increased in both depots (subcutaneous & viceral), but only the lower body subcutaneous
adipose tissue cell number increased

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22
Q

How does TZD treatments treat T2D

A

-improve ins sensitivity in peripheral tissue
(increase adiponectin?)
-promote glu uptake(increase GLUT-4)
-reduce inflammation (reduce MCP-1)
-decrease hepatic glu production (gluconeogenesis), Hb1Ac & bl lipids

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23
Q

Gene responsible for variability in obese response to 12 week aerobic training

A

PPAR-alpha gene rs 4253778

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24
Q

PPAR-alpha gene rs 4253778 genotypes and responsiveness

A

CA+AA most responded
CC lower amount of response

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25
Q

ECM remodelling is a balance between what processes

A

constructive and destructive

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26
Q

Major component of ECM

A

Collagen

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27
Q

2 primary types of proteins in ECM

A
  1. structural
    • collagens (12 types)
  2. adhesion
    • proteoglycan, laminin, elastin
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28
Q

What does decellularizing adipocyte ECM

A

-leaves ECM but no adipocyte

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29
Q

destructive enzymes

A

Plasmin
Matrix metalloproteinases (MMP)

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30
Q

What is plasmin activity regulated by

A

urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators

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31
Q

Inhibitors that regulates destructive enzymes

A

PAI-1
-inhibits u-PA and t-PA (prevents breakdown)
Tissue inhibitors of metalloproteinases (TIMP)

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32
Q

PAI-1 and obesity relationship

A

increased in obese adipose tissue and by pro-inflammatory signals (E.g. TNF-α)
=up w obesity, down w weight loss

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33
Q

Increased PAI-1 in obesity prevents

A

prevents ECM remodelling, which creates a stress in adipocyte promotes IR and impairs glu uptake

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34
Q

PAI-1KO mice

A

-protected from obesity-induced IR (increase in plasmin activity)
allowed cells to intake more
glucose in the presence of a pro-inflammatory cytokine

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35
Q

How to MMPs break down ECM

A

cleave collagen - must be cleaved by plasmin or other MMPS to become active

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36
Q

TIMP1 and obesity relaionship

A

TIMP1 expression is up with obesity and
down with weight loss

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37
Q

TIMP1 over-expression

A

-increase bl glu, ins, NEFA, liver TAG
-reduce ins stim glu uptake
(subcutaneous)

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38
Q

Dominant collagen in adipose tissue depots

A

Collagen 6

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39
Q

Affect on ECM when col 6 knocked out

A

weakened ECM
-lower body weight than obese mice at early age, lost affect after 10 weeks
-improved fasting glu levels and glu tolerance
-lower bl and liver TAG
-larger adipocyte
DESPITE BEING OBESE

40
Q

Collagen w/ insulin resistance vs sensitivity

A

-increase w diabetes
-decrease w insulin sens

41
Q

Paradox associated w weakened ECM (absense of collagen 6)

A

-larger adipocytes
-we normally think of this being associated w metabolic problems
-instead there are less metabolic problems

42
Q

Healthy vs pathological adipose tissue expansion

A

Healthy:
Hyperplasic Obesity
(problems develop eventually
Pathological:
Hypertrophic Obesity
(problems develop more quickly)

43
Q

What is adipose tissue hypoxia

A

Low O2

44
Q

What transcription factor is activated in hypoxic conditions and what does it trigger

A

HIF1 activated, triggers ER stress response

45
Q

What is HIF1α and its relationship.w obesity

A

HIF1α is a subunit of the
HIF1 transcription factor. Expression increases w obesity

46
Q

What does over-expression of HIF1α do

A

increases plasma glucose -impairs glucose tolerance

47
Q

Over-expression of adipose tissue HIF1α in animals fed a high fat diet or on a ob/ob genetic background (3 points)

A

– Increases liver TAG levels.
–Increases expression of F4/80 (a marker for macrophages) in adipose tissue.
– Increases the number of crown-like structures (CLS) in adipose tissue

48
Q

3 roles of the endoplasmic reticulum (ER)

A
  1. protein synthesis
    2.lipid droplet formation
    3.Nutrient sensing
49
Q

what assists with protein folding

A

-chaperone proteins
(BiP, calnexin, etc)

50
Q

Where do correctly and incorrectly folded proteins go

A

Correctly:
-golgi
Incorrectly:
-proteasomes (degradation)

51
Q

Where and what forms TAGS

A

3 fatty acids + 1 glycerol in ER membrane by enzymes

52
Q

where/how does the lipid droplet form

A

forms within ER membrane, buds off (takes cytoplasmic layer of the ER membrane and associated proteins

53
Q

How can lipids still be incorporated into droplet after budding off (2)

A
  1. caveolae brings lipids from out to in via receptor-mediated endocytosis, then fuse w droplet
  2. all enzymes for lipogenesis expressed in lipid droplet, TGs can be produced within
54
Q

What does SREBP acts as and what does it regulate

A

-cholesterol sensor
regulates the expression of genes involved in lipid metabolism

55
Q

What is the unfolded protein response (UPR)

A
56
Q

When is cellular stress induced

A

Cellular stress is induced with chronic nutrient overload, hypoxia, glucose & energy shortages, ↑
protein synthesis, inhibition of protein glycosylation, imbalance of Ca2+ levels, etc

57
Q

What is the unfolded protein response (UPR)

A

The unfolded protein response (UPR) is how the cell reacts to re-establish cellular homeostasis (the UPR is a protective response for the cell)

58
Q

How does the UPR re-establish homeostasis (3 answers)

A
  1. Increase the capacity of the ER to fold and translocate proteins
  2. Slow down the synthesis of new proteins
  3. And if stress is not resolved (i.e., chronic ER stress), will ultimately induce apoptosis (cell death)
59
Q

3 proteins that control UPR and their state in an unstressed ER

A

ATF-6
PERK
IRE1
Bound to BiP in unstressed ER = kept inactive

60
Q

Role of ATF-6

A

ATF-6 moves to the Golgi, -cleaved by S1P and S2P.
-releases the active ATF-6, which can then move to the nucleus.
-turn on gene express. by interacting w ERSE

61
Q

Role of IRE1

A

-Activates XBP1, turn on gene express in nucleus
-Causes the degradation of IKB and activation of JNK
–> NFkB promote inflam, gene express
-Inactivate IRS1

62
Q

Role of PERK

A

Phosphorylate eIF2α - inhibit general translation
-reduce new protein production
-exceptionsL (BiP,ATF-4,SREBP) ATF-4 = apoptosis when homeostasis not restored

63
Q

4 causes of ER stress

A

1.nutrient excess & adipocyte expansion
-increased demand for protein synthesis
2.Glucose deprivation
- insulin resistance: take up less glucose, lack of glucose causes stress
-reduced vascularization: less blood vessels, less glu to adipocytes
3. High levels of specific nutrients
- ex.diet sat fats pro inflam.
4.Inflam signal pathways
-TNFα activates the UPR via the production of reactive oxygen species (ROS).
-LPS activates the UPR by signalling via toll-like receptors.

64
Q

What is UPR-induced insulin res mediated by

A

IRE1 and JNK
(increase in phorsphorylated JNK and serine-phosphorylated IRS)
-ER stress not induced in IRE-/- cells

65
Q

What UPR markers were reduced following bariatric surgery

A

XSP1s, Phosphorylated levels of eIF2α and JNK w

66
Q

What do chemical chaperones do in targeting ER stress

A

-stabalize protein
conformation, improve ER
protein folding capacity,
and facilitate trafficking of
misfolded proteins.
-lower p-PERK, p-eIF2α, p-
JNK, and XBP1s levels
-improve whole-body markers of metabolic
health (reduce blood glucose, lower blood insulin, and improve glucose tolerance)

67
Q

Example of a chemical chaperone

A

4-phenyl butyric acid (PBA)

68
Q

Obesity-induced insulin
resistance characterized by

A

-Pancreatic β-cell dysfunction
– Impaired suppression of
gluconeogenesis in liver
– Increased lipolysis in adipose tissue
– ER stress and impaired ECM remodelling

69
Q

4 immune cells residing in adipose tissue

A

– Macrophages
– Lymphocytes (T-cell, B-cell)
– Eosinophils
– Mast cells

70
Q

Relationship
between TNFα and insulin resistance

A

TNFα influences insulin
resistance

71
Q

Positive associations were seen between TNFα
and.. (3 answers)

A

– BMI
– Fasting glucose levels
– Fasting insulin levels

72
Q

Association between and insulin resistance (IR). - how?

A

TNFα promotes serine phosphorylation of
IRS1, thus blocking an early step in the
insulin signalling pathway

73
Q

F4/80

A

macrophage marker

74
Q

What do macrophages primarily secrete

A

Pro-inflammatory adipokines

75
Q

2 macrophage phenotypes

A

M1: pro-inflammatory
-form crown like structures around dying adipocytes
M2: anti-inflammatory (less inflammatory)
-uniformly dispersed

76
Q

Anti-inflammatory adipokines (2)

A

-Adiponectin
-SFRP5

77
Q

Pro-inflammatory adipokines

A

-leptin
-resisten
-RBP4
-lipocalin
-ANGPTL2
-TNF
-IL-6
-IL-18

78
Q

Role of M1 macrophages in insulin resistance

A
  1. macrophage recruitment
  2. adipocyte-muscle crosstalk
    3.TNFa signal pathwat
    4.GPR120 mediates omega-3 PUFA benefits
79
Q
  1. Macrophage recruitment
A

-adipocytes secrete CCL2 (MCP1)
-MCP1 interacts w CCR2 (receptor on macrophages

80
Q

(1)MCP1 expression and obesity

A

MCP1 expression increase w obesity

81
Q

(1)What happens when macrophage CCR2 or MCP1 is deleted

A

reduction in macrophague infiltration, reduces inflammatory markers, improve ins sens

82
Q
  1. Adipocyte-marcophage crosstalk in lean individuals
A

– Adipocytes secrete factors (IL4,IL13) that promote a M2
phenotype in macrophages.
– M2 macrophages secrete anti-inflammatory molecules (IL10) and
possibly other insulin sensitizers
PROMOTE ANTI-INFLAM

83
Q
  1. Adipocyte-marcophage crosstalk in obese individuals
A

-Adipocytes secrete factors (TNFα,saturated fatty acids, chemokines)that promote a M1 phenotype in
macrophages.
– Macrophage secrete pro-
inflammatory molecules (TNFα, IL-1β, IL-6, etc.).
PROMOTE PRO-INFLAM

84
Q
  1. What does TNFα signal through
A

TNFα signals through it’s cell
surface receptor, TNFR.

85
Q

(3)What 2 pathways does TNFα signalling activate

A

Activation of two serine kinases
(IKK and JNK),

86
Q

(3)Two consequences of activating of JKK and JNK serine kinases

A
  1. IKK serine phosphorylates IκB, causes IκB to dissociate
    from NFκB. NFκB can then
    move to the nucleus to turn on pro-inflammatory gene
    expression.
  2. JNK and IKK serine
    phosphorylate IRS1, which
    inhibits the insulin signalling
    pathway
87
Q

(4) what is GPR120

A

omega-3 PUFA (DHA)
receptor / sensor

88
Q

GPR120 KO mice (3 points)

A

-eliminated anti-inflammatory effects of omega-3 (DHA)
(PS stimulates inflammation,
but co-treating macrophage and adipocytes with LPS and DHA (omega-3) reduced the expression of pro-inflammatory genes (TNFα,
IL-6, MCP1)
-reduced glu tolerance, needs more ins to clear bl. glu
-DHA reduced macrophage recruitment, cant occur w/o GPR120

89
Q

Evidence suggests that one can drive a M1 to M2 phenotype switch by:

A
  • Switching from a HFD to chow diet
  • Increasing n-3 PUFA consumption
  • Using a TZD
90
Q

Other immune cells in adipose tissue (3)

A

-Eosinophils (anti-inflam)
-Mast cells (pro-inflam)
-B-lmphocytes (B-cells) (pro-inflam)

91
Q

What do T-cells do

A

play an equally important role in determining the inflammatory status of adipose tissue

92
Q

IL-4

A

activates several pathways in macrophages to suppress the expression of pro-inflammatory genes and promote the alternate activation of macrophage

93
Q

What do M2 macrophages secrete

A

IL-10 - insulin-sensitizing cytokine

94
Q

What does genetic deletion of PAR δ or
KLF4 cause

A

insulin resistance

95
Q

What helps to block pro inflam signals in macrophages (2 answers)

A

-adiponectin and omega-3 fatty acids

NUTR 3360 (11 decks)

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