Lectures 19-20: Tissue specific metabolism + diseases Flashcards
Glycolysis:
- what substrate (3)
- cellular location
- Number of enzymes
- oxygen needed?
- CO2 produced?
- ATP used?
- NADH/FADH2 produced?
- ATP produced?
- carbohydrates, some AA and glycerol
- cellular location: cytoplasm
- 10 enzymes
- oxygen needed? NO
- CO2 produced? NO
- ATP used? YES
- NADH/FADH2 produced? YES
- ATP produced? YES
Pyruvate oxidative decarboxylation
- what substrates?
- cellular location
- Number of enzymes
- oxygen needed?
- CO2 produced?
- ATP used?
- NADH/FADH2 produced?
- ATP produced?
- some aa
- cellular location: mitochondria
- pyruvate decarboxylase complex (3 complexes)
- oxygen needed? NO
- CO2 produced? TES
- ATP used? NO
- NADH/FADH2 produced? YES
- ATP produced? NO
TCA cycle:
- what substrates?
- cellular location
- Number of enzymes
- oxygen needed?
- CO2 produced?
- ATP used?
- NADH/FADH2 produced?
- ATP produced?
- FA and some aa
- cellular location: mitochondria
- 8 enzymes
- oxygen needed? NO
- CO2 produced? YES
- ATP used? NO
- NADH/FADH2 produced? YES
- ATP produced? YES
oxidative phosphorylation
- cellular location
- Number of enzymes
- oxygen needed?
- CO2 produced?
- ATP used?
- NADH/FADH2 produced?
- ATP produced?
- cellular location: inner membrane mitochondria
- 4 complexes
- oxygen needed? YES
- CO2 produced? NO
- ATP used? NO
- NADH/FADH2 produced? NO
- ATP produced? YES!!
tissue specific metabolism
- skeletal muscle
- adipose tissue
- cardiac muscle
- brain (3)
- liver (3)
- skeletal muscle: uses ATP generated aerobically or anaerobically to do mechanical work
- adipose tissue: synthesizes, stores and mobilizes TG (BAT carries out thermogenesis)
- cardiac muscle: uses ATP generated aerobically to pump blood
- brain: transports ions to maintain membrane potential + integrates inputs from body and surroundings + sends signals to other organs
- liver: processes fats, carbs and prots from diet + synthesizes and distributes lipids ketone bodies and glucose to other tissues + converts excess nitrogen to urea
liver:
- which cells metabolize all 3 nutrients (which ones?)
- provides energy _________ to all tissues
- maintains balance between _________ supply and _________ demand
- has remarkable metabolic _________ in enzymatic machinery –> rapid _________ of enzymes
- enzymes are sensitive to various hormones (4)
- hepatocytes: carbs, aa, lipids
- precursors
- nutrient supply and precursor demand
- metabolic flexibility –> rapid turnover of enzymes
- insulin, glucagon, leptin, epinephrin
- nutrient supply varies with what?
- precursor requirement varies with (2)
- nutrient supply varies with diet/feeding
- precursor requirement –> level of activity and health (nutritional state)
2 types of adipose tissue?
- where?
- one or many lipid droplet?
- amount of mitochondria
white adipocytes (WAT):
- under skin, around major blood vessels and abdomen
- one lipid droplet (large spherical cell) –> squeezes mitochondria and nucleus to thin layer against plasma membrane
- a few mitochondria
VS brown adipocytes (BAT):
- under skin (chest and back)
- many smaller lipid droplets
- any more mitochondria and high blood supply –> accounts for brown color
White adipocytes:
- energy source = ?
- capable of synthesizing what from energy source?
- sensitive to which hormones (2) –> 2 different roles
- major storage of what?
- glucose
- synthesize fatty acid from glucose
- sensitive to insulin (regulated FA synthesis) and epinephrine (hydrolysis of TG to non-esterified FA)
- of TG
brown adipocytes:
- in children or adults?
- FA undergo what?
- specific protein responsible for what?
- only in children, not in adults BUT preadipocytes can differentiate into BAT in adults during chronic cold exposure (b-oxidation of own FA produces heat)
- beta oxidation
- Thermogenin (uncoupling protein 1) responsible for non-shivering thermogenesis –> produces heat but doesn’t involve muscle contraction (that causes shivering) –> to protect vital organs when babies comes out of womb
metabolism in muscle
- uses (3) for energy
- resting vs moderate activity vs vigorous (2)
- which hormone helps in using glucose from blood and glycogen?
- also has what function?
- FA, ketone bodies and glucose
- resting: FA from adipose and ketone bodies from liver
- moderate: blood glucose does aerobic glycolysis + FA and ketone bodies
- vigorous:
1. stored glycogen gives glucose –> breakdown to lactate bc blood flow can’t give enough O2 to meet high ATP demand = anaerobic glycolysis
2. phosphocreatine –> creatine produces ATP (creatine from diet or de novo (gly, arg, met)) - epinephrine
- shivering thermogenesis (muscle contraction generates heat)
during recovery from physical activity
- accumulation of ________ from anaerobic respiration –> converted to what, where? name of cycle?
- accumulation of _________ from phosphocreatine –> how do we get rid?
(buffer system for _____)
- lactate –> converted to glucose in liver (gluconeogenesis) –> Cori cycle
- creatine –> converted back to phosphocreatine by creatine kinase
- buffer system for ATP
each glycogen origin glucose gives how many ATPs during glycolysis?
3 ATPs
difference between cardiac muscle and skeletal muscle?
- cardiac = continuously active = completely aerobic metabolism (oxidative phosphorylation)
cardiac muscle:
- small amount or abundant mitochondria?
- source of E? main one vs can also use 2 others
- stored glycogen?
- sensitive to ____ deprivation –> explain
- abundant mitochondria
- FA, but can also use ketone bodies and glucose
- less stored glycogen (cannot store adipose tissue or glycogen in big quantity)
- O2 deprivation –> muscle dies without O2 supply (heart attack)
metabolism in brain:
- main fuel? which type of cells can use smtg else?
- metabolism uses around _____ g of main fuel per day
- can also use _________ as fuel
- ATP used to maintain what through which enzyme
- aerobic or anaerobic metabolism?
- stored glycogen?
- fasting/starvation –> use (2) sources of energy
- glucose but astrocytes can use FA
- 130g of glucose
- b-hydroxybutyrate
- membrane potential (Na+/K+ ATPas)
- aerobic metabolism
- no stored glycogen
- ketone bodies (from FA) and glucose (from muscle protein)
difference btw slow-twitch and fast twitch muscles
- color
- resistant to fatigue?
- low/high tension?
- rich in mitochondria?
- dense vascular system?
- acts fast or slow?
SLOW TWITCH:
- red
- highly resistant to fatigue
- low tension
- rich in mitochondria
- dense, lots of blood vessel to bring O2
- slow but steady ox phos
FAST-TWITCH:
- white
- quicker to fatigue
- high tension
- fewer mitochondria
- fewer blood vessels
- acts faster!
marathon case study:
1. first 80m: 2 sources of E
2. heart/lung take ___ min to reach what? –> what type of metabolism during this time? (____ ATP)
3. after ___ min, what takes over? (___-___ ATP)
4. by ___ min –> runner’s high = peak in _________
5. glycogen stores (______ g) sufficient for ____km –> after that = runner’s wall = minimal _________
6. so what takes over?
7. what brings him across finish line?
- ATP and phosphocreatine
- 2min to reach max capacity –> during this, not enough O2 so anaerobic glycolysis (2-3 ATP)
- after 2min –> aerobic glycolysis takes place (30-32 ATP)
- by 45min –> endorphins
- 500g –> 30km –> minimal glycolysis = pace slows down
- FA oxidation takes over –> slow in ATP yield
- motivation!
100m sprint case study:
- O2 demand is so high that what?
1. first 20 m: source of E?
2. 20-60m: 2 sources of E
3. last 40m: source of E?
- breathing required?
- breaking can NOT match
1. ATP from phosphocreatine
2. ATP from anaerobic glycolysis (produces lactate) + phosphocreatine
3. anaerobic glycolysis - technically no bc anaerobic –> but after, need breathing for gluconeogensis to replenish glycogen using Cori cycle
metabolism during fed-state:
- _________ liver
- everything regulated by which hormone? secreted in response to what? –> role?
- main source of Energy? –> to which tissue? (3)
- excess of main source of energy –> 2 pathways
- lipogenic liver
- insulin in response to high blood glucose –> role: stimulate glucose uptake by tissues
- glucose –> to brain! + muscle + adipose tissue
- to glycogen OR pyruvate –> actetyl-CoA –> CO2 AND TAG –> VLDL –> adipose tissue
how are aa and fats metabolized in liver after dietary intake?
amino acids:
- enter liver as aa –> a-keto acids: either Acetyl-CoA OR NH3 –> Urea
(acetyl-COA: oxidized for ATP OR to TAG)
Fats:
- moves from intestine to muscle or liver through lymphatic system as chylomicrons
- in muscle: FA oxidized to ATP and CO2
- in liver: TAG –> VLDL –> adipose tissue
effects of insulin on blood glucose: INCREASE or DECREASE?
- glucose uptake (muscle, adipose, liver)
- glycogen synthesis
- glycogen breakdown
- glycolysis, acetyl-CoA production
- FA synthesis
- TG synthesis
- INCREASE glucose uptake (muscle, adipose, liver)
- INCREASE glycogen synthesis
- DECREASE glycogen breakdown
- INCREASE glycolysis, acetyl-CoA production
- INCREASE FA synthesis
- INCREASE TG synthesis
Metabolism during fasting state
- ___________ liver
- decrease in blood glucose triggers release of ___________
- main pathway that will happen in liver?
- glucogenic liver
- glucagon
- gluconeogenesis –> to make glucose for the brain
fasting-state:
- 3 ways to make glucose
- why need glucose?
- glycogen –> glucose-6-P –> glucose
- proteins from muscle and liver –> aa –> pyruvate –> gluconeogenesis –> glucose 6-P –> glucose
- adipose tissue –> TG –> glycerol –> gluconeogenesis –> glucose 6-P –> glucose
- cause preferred E source of brain
fasted state:
- when no more glycogen stores –> synthesis of ________ _________ to fuel the _________
- 2 ways to make?
- what 2 substrates can make E for muscle and liver?
- ketone bodies
1. proteins from liver and muscle –> aa –> ketone bodies
2. TAG from adipose tissue –> FA –> ketone bodies - ketone bodies can make ATP for muscles too
- FA –> b-oxidation to make ATP in liver
effects of glucagon on blood glucose: INCREASE or DECREASE
- glycogen breakdown
- glycogen synthesis
- glycolysis
- gluconeogensis
- FA mobilization
- Ketogenesis
- INCREASE glycogen breakdown
- DECREASE glycogen synthesis
- DECREASE glycolysis
- INCREASE gluconeogensis
- INCREASE FA mobilization
- INCREASE Ketogenesis
- immediately after meal: glucose increase/decrease –> what 2 pathways increase (what hormone)
- 2 hours post-prandial: glucose levels increase/decrease –> what happens? (what hormone)
- 4 hours post-prandial: what hormone? what becomes the major fuel?
- glucose increases –> increase glycolysis and glycogenesis (insulin)
- glucose begins to drop –> liver glycogen releases glucose (glucagon)
- more glucagon –> FA becomes major fuel (more TG hydrolysis)
main difference btw fasting and prolonged fasting metabolism?
similar pathways –> in prolonged fasting, end-products like ketone bodies accumulate = bad
proteins containing (5 aa) sequence are preferentially depleted in liver and heart
Lys-Phe-Glu-Arg-Gln sequence
fuel reserves in body:
- normal weight 70kg man –> how many kg of adipose tissue –> estimated survival months?
- obese 140kg man –> how many kg of adipose tissue –> estimated survival months?
70 kg man:
- 15kg
- 3 months
140kg man:
- 80kg
- 14 months
2 forms of diabetes mellitus?
1. ______________ = what?
- due to what?
- usually develops when?
2. ______________ = what?
- due to what?
- usually develops when?
- what signaling is affected?
- what is sequestered in cytoplasm? why?
- Type 1 diabetes = insufficient production of insulin
- due to autoimmune destruction of b-cells
- early life - Type 2 diabetes = insulin resistance
- cells do not respond appropriately to insulin (insulin response system is defective)
- late adulthood
- INSR signaling is affected –> IRS proteins are dephosphorylated
- GLUT4 is sequestered in cytoplasm bc IRS is dephosphorylated
diabetes symptoms:
- blood glucose is elevated = increased ___________ –> excessive (2) + proteins get ___________
- in type 1, ____ breakdown is accelerated –> leads to high _____A___ ___A___ –> raises [ __ ], which leads to ___________
- what buffering system is activated? leads to what?
- breakdown of ___________ (a type of A) produces ___________, which is expelled via what?
- untreated diabetes leads to dramatic _______ _______
- osmolality –> excessive urination and thirst –> proteins get glycosylated
- fat –> high ketone bodies –> raises [H+] –> ketoacidosis
- bicarbonate buffering system is activated –> leads to altered breathing pattern
- ketone body acetoacetate produces acetone –> expelled via breath
- dramatic weight loss
why does accelerated breakdown of fat leads to high ketone bodies?
because there is an incomplete fat oxidation bc of high NADH/NAD+ radio –> inhibits TCA cycle –> leads to accumulation of acetyl-CoA –> this accumulation favorises synthesis of ketone bodies –> can’t be used as fast as they are produced = accumulation
adipose tissue is also an __________ organ bc releases what?
- these released things have what role?
- 2 examples of these things
endocrine organ
- bc it releases peptide hormones called adipokines
- carry information about fuel stores in adipose tissue to brain
- leptin, adiponectin
2 types of neurons that control eating behavior?
- example
- 2 levels of neurons
- 3 effectors?
- anorexigenic neurons –> suppress appetite: eat less, metabolize more (ie: a-MSH)
- orexigenic neurons –> stimulate appetite: eat more, metabolize less (ie Neuropeptide Y (NPY))
- arcuate neurons –> second order neurons –> effectors
- muscle, adipose tissue, liver
3 types of signals (which produce what hormones) impact eating behavior
- adiposity signals:
- leptin (adipose)
- insulin (pancreas) - Satiety signals:
- PYY (gut)
- GLP-1 (gut) - hunger ginal:
- ghrelin (stomach)
which signal activate anorexigenic neurons? vs orexigenic neurons
- leptin activates a-mSH –> eat less, metabolize more (anorexigenic)
- ghrelin activates NPY –> eat more, metabolize less (orexigenic)
which signals inhibit orexigenic neurons? anorexigenic neurons?
- insulin, PYY and GLP-1 inhibit NPY –> eat more, metabolize less (orexigenic neurons)
- NPY inhibits anorexigenic neurons (second order)
leptin –> increases/reduces appetite
- first identified in what? –> homo/heterozygous ob/ob mice –> 7 symptoms –> when leptin was injected, what happened? VS in humans?
- reduces appetite
- obese mice
- homozygous ob/ob
- ate continually, obese, elevated cortisol, shivered, infertile, insulin resistance and died early
- mice lost weight, temp returned to normal
- leptin administration to most obese people does NOT restore normal body mass –> they have high levels of leptin and maybe have leptin resistance
db/db mice are (2)
- db gene encodes what receptor in brain?
- expressed mostly where?
- obese and diabetic
- leptin receptor in brain
- hypothalamus
- ghrelin is a short term ___________ peptide from the ___________
- where are the ghrelin receptors (3)
- signaling mechanisms well understood?
- works via which signalling pathway to decrease/increase sensation of hunger
- injection of ghrelin immediately increases/decreases appetite?
- orexigenic peptide from the stomach
- brain (hypothalamus), heart and adipose tissue
- not well-understood
- GPCR –> increase sensation of hunger
- increases appetite
PYY is an _______-suppressing hormone
- peptide of ___ aa with 2 ____ residues at the end
- secreted from (2) in response to what?
- inhibits release of what from orexigenic/anorexigenic neurons
- results in increased/reduced hunger
- appetite-suppressing hormone
- 36 aa with 2 Tyr residues
- small intestine and colon in response to food entering to stomach
- inhibits release of NPY from orexigenic neurons
- reduced hunger
microbes in the gut influence what?
obesity
some microorgs create ___________ products that affect ___________ tissue
- most bacterial products are short/long chain FA (3 ex)
fermentation products that affect adipose tissue
- short chain FA (acetate, propionate, butyrate)
- propionate acts through which signalling pathway?
- stimulates and inhibits what? leading to increase in what?
- GPCR 43 and 41
1. stimulates preadipocyte differenciation to adipocytes
2. inhibits lipolysis
leading to increase in white adipose tissue (obesity)
lipid toxicity hypothesis link between obesity and type 2 diabetes
1. normal person
2. overweight person
3. pro-inflammatory state
4. chronic inflammation
5. 6. 7.
- TG diet = TG catabolized –> small adipocytes
- TG diet > TG catabolized –> larger adipocytes
- enlarged adipocytes produce macrophage chemotaxis protein (MCP-1)
- macrophages infiltrate adipose tissue in response to MCP-1
- macrophages in adipose tissue produce tumor necrosing factor (TNF) which favors export of FA
- adipocytes export FA to muscle, where ectopic lipid deposits form
- extopic lipid interferes with GLUT4 movement to myocyte surface, producing insulin resistance
counter hypothesis to lipid toxicity/obesity linking to T2DM?
counter hypothesis: insulin resistance leads to obesity
