Unit 6 - Metabolic Syndrome

Question 1

what are the hallmarks of MetS?

Answer 1

• visceral obesity (increased waist circumference)
• dyslipidemia (increased TG from insulin-stimulated synthesis in liver; low HDL b/c overloaded by TAG so increased clearance)
• HTN (reduced insulin-stimulated vasodilation, more atherogenic inflammation)
• insulin resistance (slow glucose disposal and hyperinsulinemia)
• hyperglycemia (increased propensity to DM2)
• increased blood clotting

Question 2

what is the major risk factor that predisposes MetS, and how does it lead to the rest of the hallmarks?

Answer 2

1. visceral obesity (excessive adiposity) leads to cytokine (cause low grade systemic inflammation) and NEFA release
2. insulin resistance (from NEFA and cytokines)
3. hyperglycemia (directly caused by IR)
4. dyslipidemia (b/c hyperinsulinemia stimulates TG synthesis, increasing HDL clearance)
5. HTN (not fully understood, but probably caused by visceral obesity, IR, and dyslipidemia)

Question 3

what percentage of US population will have MetS by the time they are 60 yo?

Answer 3

40%

Question 4

what causes beta-cell damage and propensity for DM2?

Answer 4

insulin resistance, dyslipidemia, and hyperglycemia

Question 5

what is insulin resistance defined by?

Answer 5

• slow glucose disposal in a GTT that measures rate of glucose glearance at defined insulin levels
• high fasting insulin level

Question 6

what are the effects of insulin resistance, especially on muscle, liver, and fat cells?

Answer 6

• in muscle: decreased glucose uptake and glycogenesis
• in liver: decreased glycogenesis; increased postprandial gluconeogenesis and glucose release
• in fat: decreased glucose uptake, LPL, TG storage, adiponectin, insulin signaling; increased lipolysis, NEFA, and cytokines

Question 7

how much do muscle and fat cells account for glucose disposal? what does this mean for IR?

Answer 7

muscle > 90%
fat cells < 2%
this means the primary consequence of IR in muscle and lvier is elevated blood glucose

Question 8

how is adipose tissue an important endocrine organ? how does it differ between fat and skinny people?

Answer 8

skinny: adipose releases more adiponectin (which decreases NEFA), and less leptin, NEFA, and macrophages
fatter: releases less adiponectin, and more leptin, NEFA, and macrophages (40-50% increase; release inflammatory cytokines)

Question 9

what is the lipotoxicity theory and what is it caused by?

Answer 9

1. FA and glucose compete for access to muscle oxidation machinery
2. regulation breaks down in obesity b/c high NEFA enter muscle cells, exceeding capacity for mitochondria to oxidize them

Question 10

what do adiponectin and leptin work together to do?

Answer 10

both adipokines stimulate beta-oxidation and lower lipolysis to reduce levels of FFA and lipotoxicity

Question 11

how do macrophage levels change in obese VS nonobese?

Answer 11

normally 5% of all cells in adipose tissue, but in obese people it accounts for >50%

Question 12

what are the 2 theories as to why insulin resistance comes about?

Answer 12

1. lipotoxicity theory (excessive adipose tissue and reduced adiponectin increases NEFA)
2. low-grade systemic inflammation theory (excessive adipose activates diverse range of stress-response and inflammatory signaling pathways)

Question 13

what does increased DAG do to insulin signaling?

Answer 13

DAG accumulation inhibits insulin signaling (increases PKC and decreases P13K kinase)

• inhibits translocation of GLUT4 in muscle
• decreases glycogen synthesis in liver

Question 14

what are the 5 main causes for DAG accumulation?

Answer 14

1. excessive caloric intake (increased lipogenesis)
2. defects in adipocyte metabolism (including lipid storage and lipolysis)
3. defects in mitochondrial function (reduced beta-oxidation)
4. gene variation in CIII (reduces LPL activity)
5. reduced AMP-activated PRO kinase signaling (decreased catabolism and increased ATP consumption)

Question 15

what role does AMPK play in modulating FA oxidation?

Answer 15

trimeric ser/thr PRO kinase allosterically activated by AMP (low intake)

• activates catabolic pathways (glucose transport, glycolysis, FA uptake, FA oxidation, mitochondrial biogenesis and autophagy)
• inhibits anabolic pathways (lipogenesis, cholesterol and TG synthesis, glycogen synthesis, PRO synthesis)
• stimulated by adipokines

Question 16

what does AMPK do to ACC and CPT1?

Answer 16

inhibits ACC (so no ACoA --> mCoA)
activates CPT1 (so FAcyl CoA is beta-oxidized, instead of becoming TGs)

Question 17

what does metformin do? what is it used to treat?

Answer 17

stimulates AMPK (phosphorylates it)

• enhances insulin sensitivity by inhibiting liver gluconeogenesis by lowering FA accumulation in mitochondria
• lowered lipid stores causes less PKC-mediated suppression of insulin receptor signaling, so more Akt, which suppresses Foxo
• commonly used to treat DM2 (less so MetS)

Question 18

what does FOXO1 have to do with insulin resistance? what happens if metoformin is given?

Answer 18

hepatic lipid accumulation inhibits insulin receptors, which decreases the amount of P13K and Akt made

• P13K and Akt usually inactivate FOXO, so if obese, FOXO1 is active, to elevate gluconeogenesis and glucose release
• metformin lowers FA accumulation by affecting mitochondria, which decreases PKC
• -the insulin receptors are now able to make P13K and Akt, which inactivate FOXO1 again, to reduce gluconeogenesis and glucose release

Question 19

how do macrophages cause insulin resistance?

Answer 19

obese people have more macrophages, which release cytokines (TNF-alpha, IL-6, PAII) that activate stress kinases (IKK-beta, JNK1, PKC) due to inflammation

• kinases phosphorylate IRS1 on inhibitory serine residues
• these residues inhibit insulin signaling

Question 20

how can severe mitochondrial dysfunction lead to FA overload and insulin resistance?

Answer 20

• over-nutrition and obesity causes oxidative stress to mitochondria, damaging them
• resulting decreased beta-oxidation causes increased DAGs (b/c acyl CoA have nowhere else to go), causing insulin resistance

Question 21

what are two diseases that link mitochondria to diabetes?

Answer 21

1. MIDD syndrome - maternally inherited diabetes and deafness are due to mtDNA mutations
2. Freidreich’s ataxia - mitochondrial disease where 20% of patients get DM2

Question 22

what do some macronutrients, like fructose and alcohol, do to contribute to IR and MetS?

Answer 22

1. metabolized primarily in liver
2. metabolism is not insulin or glucose related (so continues no matter what)
3. don’t have mechanism to form glycogen for storage (directly converted to lipids via lipogenesis)
   - increases intrahepatic lipid deposition and steatosis

Question 23

what is the difference between visceral and subcutaneous fat?

Answer 23

visceral: apple shaped with high waist:hip circumference ratio (upper body obesity); have smaller fat droplets so metabolically more active in lipolysis and TG synthesis for storage)
subcutaneous: pear-shaped with lower waist:hip circumference ratio (lower body obesity); one big droplet

Question 24

what is different about visceral fat that causes greater risk of MetS?

Answer 24

1. anatomy: intra-abdominal, so direct venous drainage to liver (NEFA et al directly and uniquely affect gene regulation, liver metabolism, and hepatic insulin sensitivity)
2. distinct intrinsic properties, mainly lipolysis: high expression of beta3-adrenergic receptors on cell surface (increases lipolytic response to catecholamines) and less responsive to insulin inhibition of lipolysis (so increased NEFA)
3. more active in secreting proinflammatory molecules

Question 25

what are the 3 methods to treat MetS?

Answer 25

1. increase AMPK
2. directly remodel lipid metabolism (decrease NEFA)
3. remodel adipogenesis (visceral –> subcutaneous fat)
4. “brown” white adipose tissue

Question 26

what are PPARs (generally speaking)? what do they do? what activates them?

Answer 26

peroxisome proliferator-activated receptor; family of ligand-activated nuclear receptors (transcriptional activators)

• regulate genes involved in lipid metabolism
• function as heterodimers with RXR, and need coactivators (involved in chromatin modulation/histone acetylation)
• activated by Fa and their derivatives

Question 27

what do fibrates do?

Answer 27

used to treat MetS by lowering TG and LDL, and raising HDL

-target PPAR-alpha

Question 28

what do thiazolidinediones (TZDs) do?

Answer 28

anti-diabetic and insulin-sensitizing drugs that mainly target PPAR-gamma

• promote insulin action, FA uptake, TG storage, and adiponectin release
• downregulate lipolysis

although improves glycemic control and decreases NEFA circulation, there is increased caloric intake and body fat gain

Question 29

PPAR-alpha

• what it upregulates
• endogenous lignads and agonists

Answer 29

mainly expressed in liver, also muscle

• upregulation of beta-oxidation enzymes
• -promotes fasting response in liver that includes gluconeogenesis and ketogenesis from glycerol released from breakdown of FFA
• endogenous ligands are unsaturated FA
• agonists are fibrate drugs

Question 30

PPAR-gamma

• what it upregulates
• endogenous lignads/agonists, coactivator

Answer 30

expressed in highest levels in fat cells, but also in liver and muscle

• no endogenous ligands, but TZD drugs are agonists
• coactivator is PGC-1 (also acts as “master regulator” of mitochondrial biogenesis)
• net effect: decreased NEFA circulation and increased insulin sensitivity
• -liver: lipogenesis and lipid storage
• -fat: adipogenesis, lipogenesis and lipid storage, adipokine production
• -regulation of whole-body insulin sensitivity

Question 31

how does “browning” fat work?

Answer 31

exercise increases fat oxidation and reduces fat accumulation

• induces expression of PGC1-alpha (key regulator in mitochondrial content and oxidative capacity, ETC)
• -over-expression induces secretion of new hormone irisin from skeletal muscle that induces subcutaneous WAT to get BAT characteristics (increased UCP1 expression, mitochondrial density, and O2 consumption)