Block 3 Adipocytes & Insulin Resistance Flashcards
What enzymes are used to convert Gly-3P to TG?
Gly-3P AT, Acyl-3P AT, phosphatase & DGAT
How is FFA release from TG stores regulated?
In fasted state (low insulin, high glucagon), via signaling from GPCR, cAMP, PKA pathway. Key enzyme = hormone-sensitive lipase (HSL)
How is FFA utilized in fed state?
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
How is FFA utilized in fasted state?
HSL activated by high glucagon/low insulin, catecholamine-stimulated adipose tissue lipolysis unopposed; FFA -> liver for gluconeo & ketogenesis, also -> mm for fuel
How are upper vs. lower body adipocytes different?
Abdominal = higher ability to store TG and release FFA by lipolysis; higher synthetic/hydrolytic capacity at smaller size vs. lower body
How do adipocyte hormones and growth factors act?
Autocrine or paracrine
What are the main adipokines?
Leptin, adipsin, adiponectin, TNF-a, IL-6, PAI-1
What is adiponectin?
Anti-inflammatory pro-insulin-secreting hormone (decreased in excess visceral adiposity)
What is the main regulator of adipocyte hormone and cytokine secretion?
Adipose tissue macrophages, in paracrine fashion
What is leptin? What inhibits its transcription?
Potent anorexigenic peptide in hypothalamus & via efferent signals to inhibit food intake (energy sufficiency signal); PPARy ligands
How do leptin levels and functions change in polygenic obesity?
Circulating levels are increased, but fail to inhibit appetite (defect in JAK/STAT signaling) = “leptin resistance”
What are the central and peripheral actions of leptin?
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)
What is adipsin/acylation-stimulating protein (ASP)?
Autocrine regulator of FFA trapping by adipocyte by increasing glucose uptake, activity DGAT, re-esterification of FFA by HSL, reduces HSL-mediated lipolysis
What is adiponectin?
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
How does TNF-a affect adipocytes and the liver? How do levels change in obesity?
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
How do hormones from visceral and subcutaneous fat affect the body differently?
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
What are PPARs?
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
What ligands affect PPAR-a? Where are its receptors, and what action does it cause?
Lig: fibrate, TZDs
Rec: adipocytes, intestine, kidney, liver, mm
Action: fat oxidation, lipoprotein expression
What ligands, where are receptors, what are actions of PPAR-y?
TZDs; adipocytes, macrophages, intestine, kidney, liver, mm; lipid synthesis, adipogenesis, carb metabolism
What ligands, where are receptors, what are actions of PPAR-d?
Fatty acids & TZDs; ubiquitous; lipid synthesis
What are glitazones (TZD)?
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
What are Pioglitazone (Actos) & Rosiglitazone (Avandia)?
Major insulin sensitizers to manage DM2; potent activators of PPARy
What TFs cause differentiation into white adipocyte?
PPARy, C/EBPa
What surface markers are present on white adipocyte precursor?
CD24+, PPARy+
What TFs cause differentiation into brown adipocyte?
PRDM16, PPARy
What TFs cause differentiation into myocyte?
Myogenin, myo D
What surface markers are present on brown adipocyte/muscle precursor?
Myf5+
What TFs may cause switching between white and brown adipocytes?
PRDM16, PGC-1, CtBP, RIP140
What TFs cause differentiation from osteoblast to osteocyte?
RunX2, Osx
What are the surface markers on white/beige and brown adipocyte embryonic stem cells?
White/beige: Pax7/Myf5-
Brown: Pax7/Myf5+
How do beige and brown adipocytes respond to energy surplus or requirement?
Beige can store excess energy; brown can dissipate energy in response to cold exposure, SNS, catecholamines, TZDs, irisin, FGF21, NPY, ANP/BNP, RALD
What is lipodystrophy?
Inability to recruit and induce terminal differentiation of pre-adipocytes = little or absence of fat
What happens when there is increased or decreased adipocyte differentiation?
Increased: increase in fat mass = obesity
Decreased: lipodystrophy
*Both show insulin resistance
When adipocytes die, what happens? How does amount of macrophages change in lean vs. obese adipose tissue?
Macrophages invade and regulate secretion of hormones and cytokines in paracrine fashion
Lean: 5-10% MFs, obese: up to 50%
What adipocyte hormones/cytokines cause endothelial dysfunction?
Increased PAI-1, FFA, adipokines
Decreased adiponectin
What adipocyte hormones/cytokines cause monocyte inflam gene exp and AD?
Adipokines
What adipocyte hormones/cytokines cause nonalcoholic steatohepatitis, sk mm insulin resistance, cardiac insulin resistance, interstitial fibrosis, LVH, and diastolic dysfunction?
Increased adipokines and FFA
What adipocyte hormones/cytokines cause beta cell apoptosis?
Adipokines, increased FFA and glucose
What are lipodystrophies?
Selective loss of adipose tissue; congenital due to loss of fun AGPAT2 (ester lysophosphatidic acid to PA); acquired cause unknown
What is the common phenotype of lipodystrophies?
Marked hypertriglyceridemia, mild hypercholesterolemia, reduced HDL, insulin resistance
What causes increased insulin secretion by beta cells?
Increased circulating glucose, ATP/ADP ratio, and NADPH (TCA cycle)
How does insulin affect liver, adipocytes, and sk mm?
Liver: increase glyc, lipo, protein synth
Ad: increased FA storage in TG, inhibit lipolysis
Sk mm: increase protein, glyc synth, glycolysis
What enzymes are dephosphorylated to become active and inactive in response to insulin?
Now active: PFK-2, PK, glyc synthase, PDH, AcCoA DC
Now inactive: PK, glyc phosphorylase
How are HSL and LPL affected by insulin?
HSL inhibited by inhibiting P, inhibiting lipolysis
LPL upregulated, increases hydrolysis of TG in CMs
What is the result of insulin resistance? What is the compensatory effect and end result?
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
What is lipotoxicity?
Lipid-induced tissue dysfunction resulting from persistent elevations in the supply, storage, and metabolism of lipid fuels
In an insulin sensitive cell, what is the normal signaling pathway?
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
What causes impaired insulin signaling?
Production of inflam cytokines (TNF-a/FFA, IL-6, resistin) by adipocytes in autocrine or paracrine mech on liver, mm
What stages of insulin signaling are reduced when insulin-resistant?
Receptor binding (TNFa), IRS proteins (TNFa, FFA), act PK (TNFa/FFA -> ceramide), GLUT4 (TNFa)
What are the candidate mediators of lipid-induced insulin resistance?
LCFA-CoA (DAG, B-ox), DAG (serine kinases, TG), ceramides (inhibit Akt PK)
What is the overall effect of insulin resistance in adipose tissue?
Increased levels plasma TG and FFA -> increased lipid deposition in liver and mm
In an insulin-sensitive cell, what effects does PPARy have?
Stimulates txn of LPL (releases FFA from TAG), FATP (transports FFA to adipocytes), ACS (converts FFA to TAG in adipocytes)
How does TNF-a cause insulin resistance in adipocytes?
Inhibits protein synthesis, inhibiting LPL, FATP, ACS actions
*Paracrine from MF or autocrine
What are clinical signs of insulin resistance and hyperinsulinemia?
Abdominal obesity, increased TG but decreased HDL, glucose intolerance, hypertension, atherosclerosis, ethnicity (SE Asia, Native American)
What is the lipid profile of dyslipidemia in insulin resistance?
Elevated total TG, reduced HDL, small dense & cholesterol-poor LDL
How does insulin resistance lead to atherosclerosis?
Glucotoxicity, lipotoxicity, and v adiponectin -> DM2, glycemic disorders, dyslipidemia, endothelial dysfxn/inflam (high sensitivity CRP), impaired thrombolysis (^PAI-1)
How are small, dense, cholesterol-poor LDLs produced in insulin resistance?
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
