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Biochemistry > Block 3 Adipocytes & Insulin Resistance > Flashcards

Block 3 Adipocytes & Insulin Resistance Flashcards

1
Q

What enzymes are used to convert Gly-3P to TG?

A

Gly-3P AT, Acyl-3P AT, phosphatase & DGAT

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2
Q

How is FFA release from TG stores regulated?

A

In fasted state (low insulin, high glucagon), via signaling from GPCR, cAMP, PKA pathway. Key enzyme = hormone-sensitive lipase (HSL)

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3
Q

How is FFA utilized in fed state?

A

Released by LPL lipolysis of TG in CM, VLDL trapped in adipose to prevent flux to tissues that don’t currently need it; 90-100% LPL-released FFA stored by adipocytes

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4
Q

How is FFA utilized in fasted state?

A

HSL activated by high glucagon/low insulin, catecholamine-stimulated adipose tissue lipolysis unopposed; FFA -> liver for gluconeo & ketogenesis, also -> mm for fuel

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5
Q

How are upper vs. lower body adipocytes different?

A

Abdominal = higher ability to store TG and release FFA by lipolysis; higher synthetic/hydrolytic capacity at smaller size vs. lower body

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6
Q

How do adipocyte hormones and growth factors act?

A

Autocrine or paracrine

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7
Q

What are the main adipokines?

A

Leptin, adipsin, adiponectin, TNF-a, IL-6, PAI-1

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8
Q

What is adiponectin?

A

Anti-inflammatory pro-insulin-secreting hormone (decreased in excess visceral adiposity)

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9
Q

What is the main regulator of adipocyte hormone and cytokine secretion?

A

Adipose tissue macrophages, in paracrine fashion

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10
Q

What is leptin? What inhibits its transcription?

A

Potent anorexigenic peptide in hypothalamus & via efferent signals to inhibit food intake (energy sufficiency signal); PPARy ligands

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11
Q

How do leptin levels and functions change in polygenic obesity?

A

Circulating levels are increased, but fail to inhibit appetite (defect in JAK/STAT signaling) = “leptin resistance”

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12
Q

What are the central and peripheral actions of leptin?

A

Central: reduces TG content in both adipose and non-adipose tissue
Auto/paracrine on adipocytes: stimulates lipolysis of intracellular TG, reduces expression AcCoA carboxylase, inhibits lipogenesis (inh exp SREBP-1)

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13
Q

What is adipsin/acylation-stimulating protein (ASP)?

A

Autocrine regulator of FFA trapping by adipocyte by increasing glucose uptake, activity DGAT, re-esterification of FFA by HSL, reduces HSL-mediated lipolysis

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14
Q

What is adiponectin?

A

Adipocyte-derived hormone, anti-diabetic, -inflam, -atherogenic
In sk mm: increases FA ox via act AMP kinase
In liver: decreases influx FFA, hepatic glucose output, increases FFA ox
In plasma: inversely correlated with TG, corr with HDL chol; reduced in obese, insulin-resistant, diabetic, dyslipidemic

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15
Q

How does TNF-a affect adipocytes and the liver? How do levels change in obesity?

A

Ad: promotes lipolysis, makes TG accessible to HDL, reduces genes of adipo/lipogenesis (NFkB), inhibits LPL synthesis
Liver: increases genes of FA synthesis, decreases genes of FA ox, stim VLDL production
*Increased in obesity -> hyperTG

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16
Q

How do hormones from visceral and subcutaneous fat affect the body differently?

A

Visc: direct to liver via portal circulation -> greater effect on metabolic function; also higher IL-6 and PAI-1
Sub: into systemic circulation; higher leptin & adiponectin

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17
Q

What are PPARs?

A

Part of superfamily of nuclear hormone receptors, with Zn-finger TFs, heterodimerize with RXR, bind PPRE in promoter of target genes, isoforms a, b/d, g

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18
Q

What ligands affect PPAR-a? Where are its receptors, and what action does it cause?

A

Lig: fibrate, TZDs
Rec: adipocytes, intestine, kidney, liver, mm
Action: fat oxidation, lipoprotein expression

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19
Q

What ligands, where are receptors, what are actions of PPAR-y?

A

TZDs; adipocytes, macrophages, intestine, kidney, liver, mm; lipid synthesis, adipogenesis, carb metabolism

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20
Q

What ligands, where are receptors, what are actions of PPAR-d?

A

Fatty acids & TZDs; ubiquitous; lipid synthesis

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21
Q

What are glitazones (TZD)?

A

Potent artificial ligands for PPARy to increase fat uptake/storage by adipocytes, increase # adipocytes to correct abnormal partitioning of FFA in mm and liver in insulin resistance

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22
Q

What are Pioglitazone (Actos) & Rosiglitazone (Avandia)?

A

Major insulin sensitizers to manage DM2; potent activators of PPARy

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23
Q

What TFs cause differentiation into white adipocyte?

A

PPARy, C/EBPa

24
Q

What surface markers are present on white adipocyte precursor?

A

CD24+, PPARy+

25
Q

What TFs cause differentiation into brown adipocyte?

A

PRDM16, PPARy

26
Q

What TFs cause differentiation into myocyte?

A

Myogenin, myo D

27
Q

What surface markers are present on brown adipocyte/muscle precursor?

A

Myf5+

28
Q

What TFs may cause switching between white and brown adipocytes?

A

PRDM16, PGC-1, CtBP, RIP140

29
Q

What TFs cause differentiation from osteoblast to osteocyte?

A

RunX2, Osx

30
Q

What are the surface markers on white/beige and brown adipocyte embryonic stem cells?

A

White/beige: Pax7/Myf5-

Brown: Pax7/Myf5+

31
Q

How do beige and brown adipocytes respond to energy surplus or requirement?

A

Beige can store excess energy; brown can dissipate energy in response to cold exposure, SNS, catecholamines, TZDs, irisin, FGF21, NPY, ANP/BNP, RALD

32
Q

What is lipodystrophy?

A

Inability to recruit and induce terminal differentiation of pre-adipocytes = little or absence of fat

33
Q

What happens when there is increased or decreased adipocyte differentiation?

A

Increased: increase in fat mass = obesity
Decreased: lipodystrophy
*Both show insulin resistance

34
Q

When adipocytes die, what happens? How does amount of macrophages change in lean vs. obese adipose tissue?

A

Macrophages invade and regulate secretion of hormones and cytokines in paracrine fashion
Lean: 5-10% MFs, obese: up to 50%

35
Q

What adipocyte hormones/cytokines cause endothelial dysfunction?

A

Increased PAI-1, FFA, adipokines

Decreased adiponectin

36
Q

What adipocyte hormones/cytokines cause monocyte inflam gene exp and AD?

A

Adipokines

37
Q

What adipocyte hormones/cytokines cause nonalcoholic steatohepatitis, sk mm insulin resistance, cardiac insulin resistance, interstitial fibrosis, LVH, and diastolic dysfunction?

A

Increased adipokines and FFA

38
Q

What adipocyte hormones/cytokines cause beta cell apoptosis?

A

Adipokines, increased FFA and glucose

39
Q

What are lipodystrophies?

A

Selective loss of adipose tissue; congenital due to loss of fun AGPAT2 (ester lysophosphatidic acid to PA); acquired cause unknown

40
Q

What is the common phenotype of lipodystrophies?

A

Marked hypertriglyceridemia, mild hypercholesterolemia, reduced HDL, insulin resistance

41
Q

What causes increased insulin secretion by beta cells?

A

Increased circulating glucose, ATP/ADP ratio, and NADPH (TCA cycle)

42
Q

How does insulin affect liver, adipocytes, and sk mm?

A

Liver: increase glyc, lipo, protein synth
Ad: increased FA storage in TG, inhibit lipolysis
Sk mm: increase protein, glyc synth, glycolysis

43
Q

What enzymes are dephosphorylated to become active and inactive in response to insulin?

A

Now active: PFK-2, PK, glyc synthase, PDH, AcCoA DC

Now inactive: PK, glyc phosphorylase

44
Q

How are HSL and LPL affected by insulin?

A

HSL inhibited by inhibiting P, inhibiting lipolysis

LPL upregulated, increases hydrolysis of TG in CMs

45
Q

What is the result of insulin resistance? What is the compensatory effect and end result?

A

Postprandial lipemia, elevated plasma FFA levels
Comp: partitioning dietary lipids to mm and liver when energy not needed
End: exacerbation of insulin resistance, ectopic lipid deposition

46
Q

What is lipotoxicity?

A

Lipid-induced tissue dysfunction resulting from persistent elevations in the supply, storage, and metabolism of lipid fuels

47
Q

In an insulin sensitive cell, what is the normal signaling pathway?

A

IRS proteins -> PI3 kinase -> protein kinases like Akt, PKB -> increased translocation GLUT-4 to cell surface -> increased glucose uptake into adipocyte
*Also stimulates SREBP-1c for adipocyte differentiation

48
Q

What causes impaired insulin signaling?

A

Production of inflam cytokines (TNF-a/FFA, IL-6, resistin) by adipocytes in autocrine or paracrine mech on liver, mm

49
Q

What stages of insulin signaling are reduced when insulin-resistant?

A

Receptor binding (TNFa), IRS proteins (TNFa, FFA), act PK (TNFa/FFA -> ceramide), GLUT4 (TNFa)

50
Q

What are the candidate mediators of lipid-induced insulin resistance?

A

LCFA-CoA (DAG, B-ox), DAG (serine kinases, TG), ceramides (inhibit Akt PK)

51
Q

What is the overall effect of insulin resistance in adipose tissue?

A

Increased levels plasma TG and FFA -> increased lipid deposition in liver and mm

52
Q

In an insulin-sensitive cell, what effects does PPARy have?

A

Stimulates txn of LPL (releases FFA from TAG), FATP (transports FFA to adipocytes), ACS (converts FFA to TAG in adipocytes)

53
Q

How does TNF-a cause insulin resistance in adipocytes?

A

Inhibits protein synthesis, inhibiting LPL, FATP, ACS actions
*Paracrine from MF or autocrine

54
Q

What are clinical signs of insulin resistance and hyperinsulinemia?

A

Abdominal obesity, increased TG but decreased HDL, glucose intolerance, hypertension, atherosclerosis, ethnicity (SE Asia, Native American)

55
Q

What is the lipid profile of dyslipidemia in insulin resistance?

A

Elevated total TG, reduced HDL, small dense & cholesterol-poor LDL

56
Q

How does insulin resistance lead to atherosclerosis?

A

Glucotoxicity, lipotoxicity, and v adiponectin -> DM2, glycemic disorders, dyslipidemia, endothelial dysfxn/inflam (high sensitivity CRP), impaired thrombolysis (^PAI-1)

57
Q

How are small, dense, cholesterol-poor LDLs produced in insulin resistance?

A

Increased levels of CLDL and CETP -> transfer TG to LDL in exchange for CE. TG-rich LDL hydrolyzed by hepatic or LPL -> small, dense, cholesterol-poor

Biochemistry (17 decks)

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