lec 3

Question 1

excess energy

Answer 1

after energy intake and output, the left over goes to excess energy

Question is: why is adipose tissue unable to store excess calories in a safe way?

Question 2

What are the excess energy stores

Answer 2

1) non-adipose stores
2) non-fat stores: liver, muscles, etc
3)Subcutaneous fat
4) visceral fat(this is unable to store excess in a safe way)

Question 3

anatomy of major fat depots in rodents and humans

Answer 3

look at pic

Question 4

What is health risk and fat correlation

Answer 4

-the health risk of adipose tissue is associated witht he LOCATION and the AMOUNT of BODY FAT
-different depots store and release fatty acids differently (due to the roles they play in physiology)

Question 5

What are the major anatomical fat depots?

Answer 5

-inta-abdominal (THIS IS VISCERAL FATS)
-lower body (gluteal, subcutaneous leg fat, intramuscular fat)
-uper body subcutaneous fat

What seperates superficial and deep abdominal subcutaneous fat (SCARPAS FASCIA)

Question 6

How do different fat depots enlarge during weight gain

Answer 6

a) Hyperplasia : increase in the number of cells
(+++ adipogenesis, +++ replication)
ex: femoral subcutaneous fat (in response to overeating this occurs) Why? -its role is to provide long-term nutrient storage

b) Hypertrophy: increase in the size of individual cells
(+ adipogeneis, + replication)
ex: visceral fat
Why? -visceral fat role is to store and release neutrients rapidly and it has limited space for growth

c) both
ex: abdominal subcutaneous fat
(++adipogeneis, ++ replication)

Question 7

What is interdepot differences of the different fats due to

Answer 7

-interpot differeneces are related to higher potentials of subcutaenous than visceral preadipocytes for replication and adipogenesis

Question 8

What is the link between obesity, insulin resistance and diabetes

Answer 8

1921: Frederick banting and Charles Best discovered insulin which can treat type 1 diabetes

1936: Sir Harry Himsworth differentiated insulin secretion and insulin sensitivity concepts
-lean early onset diabetes patients: responded rapidly to an injection of insulin with a fall in blood glucose levels
-obese later onset diabetes patients: resistant to blood glucose lowering effect of insulin

Question 9

Association between obesity and insulin resistance

Answer 9

Obesity: excess accumulation of triacylglycerol in adipose tissue)

Insulin resistance of glucose metabolism : assesed in liver and skeletal muscles

the association is that Excess energy is stored in adipose tissue, excess adipose tissue releases (or has) a substance X tat goes and signals liver nad muscle tissue and signals, causing insulin resistance

Question 10

adipose tissue secretes how much adipokines?

Answer 10

more than 50

-adipose communicates via adipokines (endocrine) and FFA (metabolic mediators) to the skeletal muscle

What types:
Adipokines: TNF alpha, IL-6, MCP-1, TIMP-1 RBP-4 increase with obesity adn induce insulin resistance in muscle

FFA’s: negativetly influence insulin sensitivty of muscles

Question 11

What does adiponectin do

Answer 11

-increases insulin SENSITIVITY of the muscles, and can prevent insulin resistance but is reduced in the obese state, so contributes to insulin resistances

Question 12

What causes defects in lipid and glucose homeostasis

Answer 12

OBESITY and LIPODYSTROPHY
WHY? -they imbalance the amount of adipose tissue and cause defects in the lipid and glucose homeostasis
(normal fat mass secretes normal adipose things so it maintains normal energy homeostasis and insulin SENSITIVITY) so ABNORMAL adipose tissue leads to abnormal adipose function leading to ->
-results in peripheral insulin resistance and type 2 diabetes

Question 13

So what is substance X?

Answer 13

Fatty acids

because when there is an influx in the presence of fatty acids in the blood streams, they are stored in other tissues like skeeltal muscle adn lvier adn this causes a reduced response of these tissues to insulin (insulin resistance)
OR causes glucose-stimulated insulin secretion to be less

Question 14

What is the normal function of adipose tissue and what is the result of losing this

Answer 14

-acts as a buffer by absorbing fats and releasing it gradually back into the bloodstream so that there is no spike

losing it:
2 ways you can lose the function
1) obesity: in obesity, fat cells are already overloaded with stored fat, so they are less able to absorb fats and release slowly
2) lipodystrophy: lack of functional fat tissue

Result of losing it:
-INFLUX OF FATTY ACIDS (nonesterified fatty acids and triacylglycerol) into CIRCULATION
-causes it to be deposited into other tissues as Triacylglycerol (TG) where it interferes with insulin responsiveness (in liver and skeletal muscles) or with glucose-stimulated insulin secretion (pancreatic beta cells)

Question 15

Positive net energy balance and effects

Answer 15

-leads to increased TG accumulation in many tissues, including adipose since buffering capacity is exceeded, leading to GLUCOLIPOTOXICITY

-increased TG in adipose leads to increased lipolysis by a mass effect

Question 16

IN what combination leads to net spillover of fatty acids to non-adipose tissue

Answer 16

-accumulation of TG in adipose tissue (increased lipoylsys) and the development of adipocyte insulin resistance

-this leads to increases in extraadipocytic triglycride storage leading to many features of insulin resistance and type 2 diabetes

Question 17

Summary of last few crads

Answer 17

eat alot and reduce calorie intake -> positive net energy balance -> increased TG in adipocytes and increased lipolysis + increased insulin resistance in adipocytes -> net spillover of Fatty acids to non adipose tissues -> liver, muscle , pancreas have TG accumulation, leading to insulin resistance and type 2 diabetes

Question 18

How is normal insulin secretion stimulated and what does insulin do

Answer 18

-glucose derivced from diet or from the body stimulates it

Role of insulin: promotes glucose uptake by skeeltal muscle adn fat, opporses hebatic glycogenolysis (glycogen into glucose) and gluconeogenesis (making glucose from non carb things), and inhibits fat lipolysis (breaking down fat into fatty acids and glycerol for energy)

Free fatty acids from adipose tissue contribute toinsuline resistance in skeletal muscle and liver

Question 19

What three processes does insulin prohibit

Answer 19

glycogenolysis (make glucopse)
gluconeogenesis (make glucose)
fat lipolysis

Question 20

What do additional fat derived signals do

Answer 20

they come from fat being broken down into fatty acids and glycerol

-,odulate insulin sensitivity and FA metabolism in liver and muscle
-examsples: TNF, Resistin, ADIPONECTIN,

Question 21

how does insulin stimulate adipose tissue fatty ascid uptake, esterification and storage

Answer 21

1) insulin promotes LPL mediated release of FFA from lipoprotein triglyceride
-LPL is an enzyme that breaks down triglycerides (from lipoproteins) into fatty acids and glycerol
-now the FFA can be uptaken by adipocytes FFA enter adipocyte through diffusion down concentration gradient adn with facilitated transport

2) Insulin stimulates the movement of FA transporters to the membrane of adipocytes
-(FAT/CD36, FABPs, FATP)

3) Insulin stimulates movement of Glut4 transporters to membrane
-causes increased glucose into adipocte
-allows there to be more g3p in the adipocyte so that the FA can be made back into TRYGLYCIERDES

4) insulin stimulates lipogenetic enzymes that turn fa back into tg
ex DGAT

5) Insulin inhibits HSl, so reduces lipolysis of TG into FA, so promotes storage

Question 22

Insulin-stimulated and contraction-stimlated glucose transport into muscle (how glucose is transported into muscle)

Answer 22

-similar systems but they are different but both result in the same thing
Insulin stimulated glucose transport:

1) insulin binds to ITS receptor at cell surface to start signalling cascade

2)glut-4 brought to the membrane of the muscle so that glucose can move in

Contraction-stimulated:
1) contraction signals it
-AMPK activation is involved as another signal

2)Glut 4 is recruited to surface (plasma membrane)

the things that activate insulin pathyway does not exercise pathway
-ie exercise does not induce phosphorylation of insulin revceptor or IRS1 (for insulin signalling aopthway to work, the insurlin receptor and IRS1(which is substrate needed in signalling) need to be phosphorylated, but exercise does not induce this phophorylation

-studies that completely knock out insulin receptor, or p13k show no effect on exercise induced glucose uptake

Question 23

If you have both exercise and muscles stimulated with supramaximal insulin what happens

Answer 23

-greater transport than with either stimulus aon

-insulin and exercise both stimulate glucose transport

-muscles that are stimulated with supramaximal insulin and exercise

Question 24

So if u have contraction and insulin, what happens

Answer 24

higher glucose transport than either alone

CALLED ADDITIVE EFFECT

Question 25

Insulin but not exercise activates

Answer 25

p13k

Question 26

Exercise but NOT insulin stimulates

Answer 26

AMPK

Question 27

p13k inhibitor blocks effects of insulin but not

Answer 27

EXERCISE because insulin activates p13k so if there is a inhibitor then insulin does not acrtivate properly but exericse stimulates ampk so pblocking p13k doesnt do antyghihg Proof: Wortmannin: a p13k inhibitor, p13k is needed to bring glut4 transporters to surface whn insulin present AICAR: compound that activates AMPK (needed to be activated to move glut4 to membrane for contraction pathway) When applied wortmannin to aicar, it did not drop the glucose transport, neither did applying it to contraction it self, but whne applied to insulin IT DROPPPEDDDDDDD

Question 28

soooo what does wortmannin block

Answer 28

wortmannin blocks insulin signaling (by inhibiting PI3K), but it does not block AMPK-related pathways.

Question 29

AICAR + Insulin effects?

Answer 29

Yes it has additive effects, more glucose transport (uptake in muscle)

Question 30

AICAR + Contraction effects

Answer 30

no additive effects, together it does not increase transport (glucose uptake)

Question 31

Contraction plus insulin effects

Answer 31

increased glucose transport (uptake) (additive effects)

Question 32

what has higher muscle glucose uptake contraction or insulin

Answer 32

insulin, but c and i combined is even higher and aicar and insulin combined is EVEN higher

Question 33

mice studies and glucose transport

Answer 33

Leptin deficient obese rats (called zucker rats): insulin resistant but have normal contraction glucose uptake (OB/OB mouse, insulin resistant because of obesity (visceral adiposity) mice with inactive AMPK expression: normal insulin response, glucose uptake impaired (contraction pathway impaired, Glucose uptake is impaired, meaning the AMPK pathway (used during exercise or energy stress) is dysfunctional due to inactive AMPK.) LKB1 (Upsteam AMPK kinase, it activates AMPK) KO mice: insulin sensitivity fine, contraction mediated glucose uptake impaired Insulin receptor knockout mice: contraction mediated glucose uptake normal but insulin doesnt work

Question 34

insulin increases review

Answer 34

free fatty acid intake into cell by incresing transporters on membrane more fatty acid means more uptake insulin increases LPL activity which means that more tg are broken into fatty acids AND it increases the transporters on the cell too FA transporters

Question 35

AICAR is a what for contraction

Answer 35

mimetic stimilates the same pathway

Question 36

Current Understanding of the Signaling Pathways Involved in GLUT4 Translocation with Insulin or Contraction

Answer 36

look at notes on notability

Question 37

what is the insulin pathway that leads to glut4 being moved

Answer 37

1) insulin binds to the alpha receptors 2)tyrosine residues on the beta are phosphorylated and tyrosin kinase on the beta is activated 3)tyrosine kinase activates IRS1 4)IRS1 binds to P85 of P13k 5)13k phosphorylates and activates p110 WHICH phophorylates pip2->pip3 6)increased pip3 due to p13k causes pdk1 activation and AKT recruitment 7)AKT phosphorylated by ppk1 (not fully, needs rictorMTOR kinase) 8) PDK1 also phosphorylates atypical PKC 9) PKC and Akt together phosphorykates AS160 and inhibits rab which increases the movement of glut4 storage vesciles

Question 38

As160

Answer 38

-phosphorylated by atypical pkc and akt -gtpase activating protein -active ewhen dephos -another isoform of itis TBCD14 What is the difference between as160 and tbcd14 -tb becomes phosphorylated in response to NOT ONLY INSULIN but also cont4ractile activity and pharmacological activation of ampk and AICAR

Question 39

what happens in the absense of insulin

Answer 39

low akt low pkc, so as160 is dephosphorylated so gtpase is active... rab proteins will be bound to gdp so inactive so no signal to translTE glut 4 to mem

Question 40

what does less gtpase activty mean

Answer 40

means that signal will be sent to glut 4 to mem, because more rab gtp so that is the signal gtpase hydrolyses gtp to gdp so when as160 active (when dephos) it will be more rabgdp so inactive but when as160 dephosphorylated it is inactive so more rab gtp and this is the signal INCREASED RAB GTP is the signal intiates the glut 4 to mem

Question 41

at what step does the insulin pathway and the contraction pathway converge

Answer 41

at the as160 step... if as160 active then it will not move glut to mem if as160 inactive then it will move it to mem remembr as160 is inactive when it is [phosophorylated

Question 42

so what inactivates (in this case to inactivate u need to phophoryate) as160 and tbcd14

Answer 42

atypical pkc and akt also contractile activity pharmalogical activation of AMPK with AICAR soooo insulin resistance can be treated with AMPK (ampk can be a ptentioal therapeutic target for insulin and type 2 diabetes)

Question 43

Causes of insulin resistance in skeletal muscle

Answer 43

1) increase in intramyocellular lipid accumulation and fatty metabolites (DAGs, fatty acid co a) -if u have too much fatty acid coming in, it will go and block the glut 4 into to the membrane and impair the insulin pathway 2) reduction in fatty acid oxidation -Lipid accumulation in muscle can be attributed to a) increase circulating plasma FA (adipose tissue storage is affected) b) increased rates of Fa transport into muscle c)reduced rates of fatty acid oxidation (using it less, there is impaired rates of fatty acid usage so makes it less and therefore more is stuck)

Question 44

in a healthy active individual using free fatty acids as a substrate to fuel

Answer 44

intramuscular triacerol glyc will be diminished so they need to be replenished during the next eating period, so this pathway needs to work

Question 45

both the fatty acid transport of transporter to membrane and the glut 4 transporter are moved at the same time but are in different things

Question 46

white adipose tissue can be impaired as it gets too much fatty acid so this spillover is what is going to muscle meaning

Answer 46

the muscle will get an over accumulation of lipids as well as long as the amount of circulating fatty acids increases

Question 47

Redistribution of the fatty acid transporter to the plasma membrane in insulin resistant muscle which allows for more rapid entry of fatty acids into cell

Answer 47

in healthy individuals: less and smaller TG stored, more contact with mitochondria to allow for increased uptake and oxidation (usage) In moderate obese, type 2 diabetes individuals: bigger tri stores, less contact, more transport of fa transporters to membrane, increased ceramides and dags as welll, permanent redistrubitoon to the membrane (more fat being taken up to our muscles at a higher rate (sedentary person) , more comes in because these recylcing mechanism of the tranporters dont work no more in severe obese: same as moderate but even worse, greater lipid stroage, because much greater delivery, and mitchondria function is impaired in this state, ability to oxidize is impaired,

Question 48

is more contaft with mitochondria better

Answer 48

yes because it means more chances of oxidation

Question 49

little summary

Answer 49

eat too much, the adipose tissue stores are full, circulating plasma tri increases

Question 50

Exception to the relationship between increased intrmyocellular TG and insulin resistance

Answer 50

-highly trained endurance athletes have higher lipid storage droplets in muscle than sedentary / diabetic individuals, yet they are far more insulin sensitive -type 1 are more insuine senstive but they have 3 fold higher content of intramyocellular tg than type 2 muscle fibers HOW??? -in enduracne trained athelete, there is a high capacity for lipolysis (lipid oxidation) due to lipid droplet being in very close content with mitochondria, so they have a high OXIDATIVE CAPACIGTY and HIGH BETA OXIDATION CAPACITY, high turnover rate -Rates of fatty acid oxidation and IMTG turnover are high in tpye 1 fibres of muscles due to the differences in lipid droplet MORPHOLOGY (size and coating proteins) as well as their location (next ot mitochondria) and the content of mitochondria adn the ointeraction)

Question 51

are type 1 or type 2 muscle fibers more insulin sensitive

Answer 51

type 1, but type 1 (oxidative) has 3 fold higher content of intramyocellular TG compaired to type 2 (glycolyic)

Question 52

look of insulin sensitive trained individual muscle fibers vs insulin resistant obese individual muscle fibers

Answer 52

INSULIN SENSITIVE TRAINED: type 1: large number of small LD in IMF region (closer to core fiber mito) -more mito contact with LD -high IMTG turnover -decreased dag and ceramide INSULIN RESISTANCE obese individual: -larger SD in SS (subsarcolemma) region (near cell mem) -fewer mito and decreased contact with LD -especially in type 2 -lower IMTG turnover with exercise -increased DAG

Question 53

why is there more dag and ceramides in obese individuals

Answer 53

because it is not being used so everything is being stored, whereas for the healthy individuals it is being oxidized so it is being used more

Question 54

does increased tag mean increased dags and ceramides

Answer 54

NO because in enduraced trained athletes there are more tags but not dags and ceramides, this is because the rate of fatty acid oxidation is high for these indivudals so hey have more tags to use cause more gets used up quickly more tags does not cause insulin resistance n high endurance trained ones because u are not storing dags and ceramides, it is the dags and ceramides responsible for insulin resistance, there is more tags and more mitochondria

Question 55

so does tags cause it or dags and ceramides

Answer 55

dags and ceramides causes insulin resistance

Question 56

less beta oxidation and less mitochondrial density means

Answer 56

increased dags and ceramides

Question 57

what happens in a unhealthy insulin resistance muscle

Answer 57

decreased beta oxi and decreased mito so increased dasg and ceramides this goes and activates PKC theta which goes and phosphoryltates serines residues on the insulin resceptor substrate and the beta subunit of the insulin receptor this causes less tyrosin phophorylaion when insulin binds and less tyrosine kinase of the subunit, so less irs1, decreased pi3k activitty, decreased pip, decreased pdk1 and akt, and less phos of as160 so less inhibition of gtpase on rab so less rap GTP so decreased translocation

Question 58

decreased glycoen synthesis and storage because insulin regulates enzyme that regulates it

Answer 58

-phophorylation of glycogen synthesis kinase normal AKT phos gsk3 which inhibits it, so this means that there is less phosphorylation of glygoen synthase so increased glycogen synthesis now we have less akt so less phos of gsk3 so it is active and it goes and phosphorylates glycogen synthase which inhibits it making less glycogen synthesis

Question 59

Why does accuumulation of intramyocellularlipids occur?

Answer 59

1) increased circulating FFA woth obesity and insulin resistance (less uptake in other places like adipocytes due to hypertrophy of it) 2)omcreased capacity for FFA into muscle due to increast FAT/CD36 on plasma mem 3) Decreased capacity to oxidize fats due to low mitochondria

Question 60

What do fatty acid metabolites activate

Answer 60

PKCtheta, which causes serine phosphorylation of the insulin receptor beta subunit and inactivation of IR and IRS1 which leads to decreased AKT which means taht GSK3 is not phosphorylated meanign that it is active meaning that it is phos glycogen synthase which causes decreased glycogen storage and also inactivate of insulins affect on muscles

Question 61

what are the two things that can explain decreased glycogen synthesis in a insulin resistant muscle

Answer 61

1) increased dags and cermides that inactivate glygoen synthase 2) decreased glucose uptake into the muscle to store as glycogen due to inactivation of the pathway that leads to glut4 transporter to the plasma membrane

Question 62

LIVERRR

Question 63

at rest the liver has a _____ rate of gluconeogenesis and glygoenolysis

Answer 63

High because it is producing glucose to prvent low resting blood levels from dropping (to hypoglycemic) (when insulin is low) when we eat, glucose rises and insulin rises so we dont need to break down glucose anymore so that we need to stop this pathway of the liver so that we can reduce the sugar, insulin signalling is supposed to do this -typically after30 mins after eating it is surpressed, , it takes up glucose to replenish glycogen stores

Question 64

When liver is insulin resistant

Answer 64

-we eat a meal, insulin is released, but we dont get a liver glucose output reduction so we get further hyperglycemia

Question 65

what is fasting hyperglycemia related to

Answer 65

-increaed rates of endogenous glucose production (25%) which could be due to increased gluconeogensis and glycogenolysis impaired fasting glycemia is partly due to this

Question 66

the reduction in glycogen syntehsis in type 2 diabetes leads to lower

Answer 66

lower glycogenolysis (cuz less glycogen is being made) and 60% increase in gluconeogenesis, so means increase in liver glucose is due to not breaking down but continuing to make glucose

Question 67

IN type 2 diabetes inidivduals what are the results of hepatic glucose production in comparison to normal people

Answer 67

in control (normal people): mostly gluconeogenesis but decent amouht of glycogenolysis contributes to hepatic glucose production in type 2: barely any glycogenolysis (because defect in glycogen storage), mostly gluconeogenesis

Question 68

liver pathway of type 2 insulin resistant individuals

Answer 68

increased dags and ceramides activates PKC isoform serine phophosyrlation of serine residues of the beta subunit of insuloin receptor, and IRS2 decreased tyrosine phos of ir and irs2 decreased pip3 and akt decreased akt means decreased phos of gsk3 so less inhibition of it so it phos glycogen synthase so decreased glycogen synthesis therefore lessglycogen stores and less glycogenolysis

Question 69

How doe liver usually turn off or reduce gluconeogenesis and what happens when impaired

Answer 69

through regulation of FOXO phosphorylated foxo keeps it in cytosol so it cant go to nucelus and do things to transcribe or repress genes, Impaired insulin causes LESS phosphorylation of FOXO so it is in the nucleus now -it leads to INCREASED PEKPEK and Increased G6PAse (gluconeogenetic genes!!!) so increased gluconeogenesis!) normallyinsulin signalling surpresses this. S

Question 70

Adipose hypertrophy is theunderlying cause of tpye two diabtetes

Answer 70

true

Question 71

types of adipocytes in individuals

Answer 71

lean insulin sensitive: small adipocytes, normal capacity for TG, fatty acid getting taking into muscle is being oxidized, these adipocytes have few macrophages and few imune cells Overweight individuals: adipocytes enlarge, hyperplasia in visceral tissue) more of these small cells and they maintain fat storage capacity, no problems Even more overweight: once the adipocytes get to a certain size, it changes and they have different genes expessed such as MCP-1 (in visceral adipose), high scpression of this and it attracts more macrophages to enter the adipose tissue, they are immune cells and they express high tnf alpha (high inflamatory cytokine), it causes inflammation in visceral adipose tissue ebcause of the reduce capacity of adipogenesis and replication, high TNFalpha can explain impaired ability to store fat and increased lipolysis and release from adipose tissue (spillover)

Question 72

Hypertrophy of adipose leads to

Answer 72

increased macrophages, increased visceral inflammation, increased tnf alpha, which impairs storages of tg in adipocytes, impairs lipolysis so more fa is released out fo adipocytes so there is more ectopic fat in the blood so insulin resistance.

Question 73

increasing by hyperplasian for adipose cells in ob/ob mouse made the mice

Answer 73

obese but not insulin resistnat

Question 74

how does tnf alpha impair tg storage and insulin resistance

Answer 74

-PPAR-gamma is involved in regulation of genes that encode for proteins that are involved in TG syntehsis and storage and regulation of lypolysis PPAr gamma expresses those genes, so in healthy individual we have lots of this expression to have normal storage and lipolysis, TNF messes with ppargamma, -decreases ppargamma transcription, less produced, tnf does to ppar gamma 1) decreases the transcription 2) degrades Ppar gamma mrna before it is even translated 3) activates signalling pathway that reduces translation of ppar gamma 4) activates cascades that degrades the rpotein (ubiquitylation) and proteosomal degredation of the protein

Question 75

small adipocyte

Answer 75

-insulin sensitive -glut 4 is moved to membrane -glucose uptake increased -usd to make alpha glycerol phosphate the backbone of TG -insuline increases lipoprptein lipase activity, causes lipoylsis that can be taken up in adipocyte, -fatty acid transporeters are also moved to the membrane -lots of ppar so lots of tg synthesis enzymes -decreases lipolysis when eating food by akt when activqated targets phosphodiesterase 3, which breaks down cyclic amp so less activation of lipolytic enzymes so lipoylysis is turned off

Question 76

enlarged adipocytes

Answer 76

-enflamed -increased Mcp1 so increased tnf alpha -decreased ppar gamma(impaired tg synthesis now) -insuline resistance -impairs glut 4 to membrane and decreases glut 4 expression -decreases perilippin (coats lipid droplet, unless phosphorylated by HSL , it blocks lipolysys, soif hsl doesnt do that, it is having large lipolysis cus enzymes can accesss kipid droplet) -ncreases cyclic amp by increases adenyl cyclase,

Question 78

TZD

Answer 78

increases ppar gamma expression -diabetes med that can be prescribed -side effect is weight gain, improved TG storage capacity and surpression of lypolysis, can maintain the functionof adipocyte

Question 79

when adipose tissue increases in sizeby hypertrophy

Answer 79

mcp1 increases and other adipokines change their levels, increase when adipokines enlage -resistin, TNF, RBP4 (cause insulin resistance in muscle and liver) -released and circulate in the blood and have receptors on muscle, liver and other tissues and cause insulin resistance -activate by phosphorylates serine kinase which inhibits irs1 and ir (beta subunit), leading to the closure of pathway (same thing as dags and ceramides), leads to less tyrosine phosphorylation

Question 80

so increased dags, ceramides and adipokines from the adipocytes that are hypertrophy

Answer 80

all lead to increased insulin resistance through the same way of serine kinase phosphoryaltes ir and irs1

Question 81

Mitochondrial disfunction in obesity

Answer 81

h202 productions from mito in skeeltal -higher in obeese than in lean following high fat meal -higher oxidative stress on muscle in obese individuals (4h post fat meal) -oxidative stress activates the serine kinase pathway too which phos serine on irs and ir

Question 82

what does more h202 mean

Answer 82

more oxidative stress

Question 83

summarizing the link between oesity and insulinn resistnace in muscle

Answer 83

what causes insulin resistnace in obese 1) impaired white adipocyte function -increased mcp1, recruitment of macrophages and increased tnf alpha... -means likes ppar gamma so less tg synthesis enzymes so cannot store tg in adipocyte so it is released into circulation through increased lipolysis 2) free ffa go to muscle and liver -ectopic fat deposition so dags and ceramides increase, this causes serine kinase again -lack of turn over of the lipid droplets what causes this, not the presence, but its their location , morphology, etc that leads to the accumulation of dags and ceramides -remember the pathway and hhow less glut 4 translocation and how it is impaired 3) free fatty acids impair mitochondrial fucntion and increases H202 leading to oxidative stress so serine kinase pathway acivated -acute increases in circulating ffa leads to increased oxidative stress(ROS), specifically h202 coming from mito, Reactive oxygen species (ROS) activateserine kinase pathway and phophosyraltes serine reidudes on irs 1 and ir 4)hypertrophy of adipocyte (growing of it) leads to the release of more adipokinse such as rbp4, tnf and resistin, which also decreases the expression of adipokines that improve insulin sensitivity and initiate serine kinase pathway -decrease expression of one adipokines that enhances insulin sensitivity (Adiponectin is decreased) -bind to receptors on muscle and activate stress kinase, impairs insulin signalling pathway

Question 84

adiponectin

Answer 84

enhances insulin sensitivity

Question 85

if u have obesity without inflammation does all of this happen

Answer 85

no

Question 86

even if someone is insulin resistant will the ampk contraction pathway work

Answer 86

yes, aicar increases ampk activity similary in both obese and type 2 diabeeti skeletal muscle from rodents and humans releative to lean control so if there are defects in ampk then this would contribute to insulin resistance

Question 87

glut 4 levels during basal, insulin and exercise

Answer 87

lean rats basal: works fine nroaml levels insulin: increased glut 4 add exercise: increased from basal but less than insulin obese rats: basal: bit less than lean glut 4 levels insulin: little increase fom basal, not nearly as much as lean exercise: drastic increase, even more than lean

Answer 88

TZD: work by counteracting the affects of tfn alpha o ppar, so preventing fatty acid spillover andmaintain the storage function of adipocytes adiponectin: mostly improves insulin sensitivity through ampk Lpetin: increases insulin sensitivity through ampk but can develop resistance to it in muscle and hypothalamus resveratrol: improves insulin sensirivity by ampk and PGC1 aplha which increases mitochondrial content

Question 89

mech that leptin and adiponectin used to stimulate fatty acid ocidation and reduce lipid accumulation in muscle and liver

Answer 89

activates ampk whicj inhibits acc which decreases conversi ofacetyl co a to malyno coa so less inhibitions of CPT1 and increased fatty acid transport to mitochondria and more oxidation and AMPK increases glucose uptake into the cell just knpw ampk increases fatty acid transport into mito causing more beta oxidation, leads to less chance of dag and ceramides to be produces if the fatty acids are being taken into the mito so goodbecause dags and ceramides wont serine phosphorylate and normal insulin signalling will occur

Question 90

Chronic obesity reduces adiponectin

Answer 90

yes and leptin can cause resistance of it if used too much

Question 91

Review

Answer 91

-pos energy balance and obesity cause lipid toxicity (increased circulating free fatty acids), tg storage cant happen, lipolysis causes it to go out, so pancreativ beta cells take it up making it to have decreased insuln secretion and apoptoxys due to oxidative stress -liver gets dags and ceramides so excessive gluconeogeneisis and decreased glycogen synthesis, this dumps in muscle -dags seramide and insulin resis in muscle finally -insulin resis of liver and muscle and defective insulin secretion leads to problems with regulating blood glucose levels which leads to hyperglycermia,hypercly leads to major complications and further impairs pancreas, liver and muscles

Question 92

drugs that help

Answer 92

1) Sulfonylureas: increase insulin secretion in the pancreas, the higher the glucose the more effective this drug is, use the bodies insulin to help hyperglycemia -targeting the symptom not the issue at hand diadvantage: a) hypoglycemia b)weightgain 2) TZD -pos effects of insulin sensitivity in miuscle and liver -main effect is decrease lipolysis of tg, by activating ppar gamma, leading to more tg storage in this tissue improve lipid storage capacity, prevent enhanced lipolysis, will counteract effect of inflammation so less lipid toxicity, so less pan issues, and liver and muscle -targets cause of type 2 diabetes and retain pancrease function -increase glucose uptake advantagesL a)no hypoglycemia b) reverses the effects of type 2 c) possible beta cell preservation disadvantage: weight gain 3) Metformin: -decrease hepatic glucose production -lowers gluconeogenesis in liver -lower fasting blood gkucose and improves insulin siensitivty -managessymptioms not problem -can also activate ampk advantages: a)weightloss b) no hypoglycemia 4) alpha glucosidase inhibitors -delay intestinal carb absorption -delays the rise of blood glucose -treat the symptom all these drugs are affective at lowering HAtc (hyperglycermia_ levels when prescribed on their own (equally effective toher than alpha glucosidase which is half as effective) combo of 2 will furhter reduce 1-2% beyond a monotherapy by itself

Question 93

sulfonylurea and alphaglucosidase

Answer 93

can be prescribed, what do u have to be cautious of -hypoglycemia is a thing of sulf, so if u are hypoglycemic and want to eat something to increase sugar levels, u have to eat very simple carbs or else the alpha will slow down the carb absorption

Question 94

Convential tratements for type 2 diabetes do not provide adequate glycemic control to prevent the long term progression of the disease

Answer 94

diet: clincially not effective, effectivenes to reuce glucose levels decreases over time sulph: met insulin effectivenes over time decreases because u are not treating the cause so losing insulin sensitivity over time

Question 95

TZD

Answer 95

if u use it early before beta cell disfucntion (once u do, its not reverseable), if u get it early enough u can prevent disfunction and can reverse and increase beta cell function, treating symptom and improving insulin sensitivity of muscle and lvier and everything

Question 96

resveratrol

Answer 96

improves mitochondrial function and protects against metabolic disease by activating sirt1 and pgc1 -SIRT1 activation is a promising therapeutic approach for treating disease of aging such as type 2 diabetes

Question 97

HSP72

Answer 97

-protects against obesity induced insulin resistance -heat treatment imprves glucose tolerance and prevents skeletal muscle insulin resistance in high fed diet so it can inhibit obesity induced JNK and IKK and could be a potential therapeuatic treatement for obestiy