The Fed-Fast Cycle

Question 1

the absorptive/ well-fed state an anabolic period ?

Answer 1

due to the increased insulin-glucagon ration along with the readily available substrates circulating. available nutrients are captured as glycogen, TAG, and protein.

Question 2

when do allosteric changes occur ?

Answer 2

allosteric changes usually involve rate-limiting rxns

Question 3

how is glycolysis allosterically regulated in the liver following a meal ?

Answer 3

glycolysis is stimulated following a meal by an increase in fructose 2,6-bisphosphate, an allosteric activator of PFK-1. In contrast, GLUCONEOGENESIS is INHIBITED by fructose 2,6-bisphosphate, an allosteric inhibitor of fructose 1,6-biphosphatase

Question 4

give examples of how insulin/glucagon can be responsible for induction and repression of enzyme synthesis.

Answer 4

insulin stimulates synthesis of enzymes like ACC and fatty acid synthase.

glucagon stimulates synthesis of PEPCK that converts oxaloacetate back to PEP (for gluconeogenesis)

Question 5

liver is normally a glucose-producing rather than a glucose-using tissue. is that true after a carb-rich meal?

Answer 5

No. after a carb-rich meal, the liver becomes a net consumer, retaining roughly 60 of every 100 g of glucose presented by the portal system. this increased use reflects increased glucose uptake by the hepatocytes. their insulin-independent glucose transporter (GLUT-2) has alow affinity (high Km) for glucose, and therefore, takes up glucose only when blood glucose is high.

Question 6

increased phosphorylation of glucose:

Liver in the absorptive state (well-fed):

indicate the mechanisms by which hepatic glucose metabolism is increased in each of the following:

Answer 6

high extracellular glucose–> high intracellular glucose –> glucokinase phosphorylates glucose –> G-6-P !

Question 7

increased glycogenesis:

Answer 7

abundant G-6-P is an allosteric activator of glycogen synthase

Question 8

increased activity of PPP

Answer 8

abundant G-6-P comibined with the use of NADPH stimulates PPP

Question 9

increased glycolysis

Answer 9

once PDH is activated, it favors acetyl coA production; acetyl coA is then either involved in TCA cycle to harness energy for glycogen production or is involved in fatt yacid synthesis

fructose 1,6-bisphosphate is inhibited and other glycolysis enzymes.

Question 10

increased fatty acid synthesis

Liver : well-fed state

Answer 10

abundance of acetyl coA (from fatt yacid and amino acid synthesis), NADPH (PPP), and activation of ACC via citrate: its allosteric activator. malonyl coA inhibits CPT-1 of fatty acid oxidation as well.

Question 11

liver: fed state

Answer 11

Pyruvate cyt–PDH–> acetyl coA mit –> plus oxaloacetate –> citrate mit –> citrate cyt – ATP citrate lyase –> oxaloacetate plus acetyl coA. oxaloacetate –malate dehydrogenase –> malate – malic enzyme – > pyruvate.

Question 12

Liver fed state

Answer 12

TAG synthesis is favored becasue fatty acyl coA’s are available both from de novo synthesis from acetyl coA and from gydrolysis of TAG component of chylomicron remnants removed from blood by hepatocytes. glycerol-3-phosphate, the backbone for TAG synthesis is provided by glycolysis. the liver packages TAG into VLDLs secreted into the blood for extrahepatic tissue use like muscle and adipose.

Question 13

Liver Fed state

Answer 13

in absorptive state, more amino acids are pressent than the liver can use in synthesis of proteins and other nitrogem-containing compounds. surplus amino acids not stored but released into the blood for other tissues to use in protein synthesis or deaminated and resulting carbon skeletons being degraded by liver to pyrvate , acetyl coA, or TCA cycle intermediates –> can be metablized for energy or used in FA synthesis. leucine, valine, isoleucine (branched amin acids) pass through the liver unchanged.

Question 14

liver well-fed state

adipose tissue ? (general)

Answer 14

adipose tissue is second only to liver in its ability to distribute fuel molecules. 70-Kg man, white adipose tissue WAT weighs about 14 Kg.

Question 15

liver fed state

Answer 15

elevated insulin in absorptive state –> increased glucose influx into adipocytes via insulin-sensitive GLUT-4 recruited to cell surface from intracellular vesicles. glucose phosporylated by hexokinase.

Question 16

liver fed state

Answer 16

abundant intracellular glucose –> enhanced glycolysis –> serves synthetic function of providing glycerol-3-phosphate for TAG synthesis

Question 17

liver fed state

Answer 17

adipose tissue can metabolize glucose by means of PPP, producing NADPH for fatty acid synthesis. HOWEVER< in humans, de novo synthesis is not a major source of FA in adipose, except when re-feeding a previously fasted state. remeber that liver is the primary source of de novo synthesis of FA.

Question 18

liver fed state

Answer 18

most fatty acids added to TAG stores of adipocytes after cinsumption of a lipid containing meal provided by degradation of dietary TAG in chylomicrons sent out by gut and endogenous TAG in VLDL sent out by liver. FAs released from lipoproteins via lipoprotein lipase LPL; extracellular enzyme attached to capillary walls in adipose and muscle tissue. LPL is upregulated by insulin

Question 19

resting skeletal muscle fed state

Answer 19

fed state muscle takes up glucose via GLUT 4 for energy and glycogen synthesis and amino acids for protein synthesis. energy metabolsim of skeletal muscle is unique in being able to respond to body demands of STP that accompanies muscle contraction. skeletal muscle, despite its potantial for transient periods of anaerobic glycolysis, is an oxidative tissue.

Question 20

primary source of energy in muscles fed state?

Answer 20

1# glucose

2# FA’s released from chylomicrons and VLDL via LPL

Question 21

amino acid meabolism in the muscle fed state ?

Answer 21

the muscle is the principal site for degradation of BCAAs (leucine, isoleucine, and valine)because it contains the required transaminases. the BCAAs escape metabolism by the liver and are taken up by muscle, where they are used for protein synthesis.

Question 22

FASTING state transition ?

Answer 22

fasting begins if no food is ingested after absorptive period. plasma levels of glucose, amino acids, and TAG fall –> insulin release –> decreased insulin-counteregualtory hormone ratio and decreased substrate availability –> CATABOLISM –> degradation of TAG, glycogen, and protein

two priorities:

1# the need to maintain adequate plasma levels of glucose to sustain energy metabolism in brain, RBCs , and other glucose-dependent yissues.

2# the need to mobilize fatty acids from adipose tissue and synthesis and release of ketone bodies from liver to supply energy to other tissues.

Question 23

Liver fasting state CARBS

Answer 23

liver responses first by

1# glycogen breakdown –> glycogen phosphatase mobilized

2# gluconeogenesis –> carbon skeletons for gluconeogenesis derived primarily from glucogenic amino acids, lactate from muscle, and glycerol from adipose tissue. decreased availability of fructose 2,6-bisphosphate which actually inhibits fructose 1,6-bisphosphatase–> fructose 1,6 bisphosphatase actiavted along with PEPCK and Pyruvate carboxylase.

note that decreased fructose 2,6-bisphosphate inhibits glycolysis at PFK-1 step

Question 24

liver FATSED state *fat metabolism*

Answer 24

oxidation of fatty acids (TAG hydrolysis) is the major source of energy in hepatic tissue in the postabsorptive state.

• NADH inhibits the TCA cycle
• acetyl coA is an allosteric activator of PC and allosteric inhibitor of PDH (favoring use of pyruvate in gluconeogenesis)

Question 25

liver FASTED state *ketone body synthesis*

Answer 25

the liver is unique in being able to synthesize and release ketone bodies for use as fuel by peripheral tissues but not by the liver itself because the liver lacks thiophorase

during first days of fasting when the concentration of acetyl coA from FA synthesis exceeds the oxidative capacity of the TCA cycle–> coA released which sustains TCA cycle

they can be used by fuel in most tissues, including the brain once their concentration in the blood is sufficiently highwhich reduces the need for gluconeogenesis that exhausts amino acid carbon skeletons of essential protein.

Question 26

adipose tissue FASTING state *Carb metabolsim*

Answer 26

insulim-sensitive glucose uptake via GLUT 4 into adipocyte and its subsequent metabolism are depressed due to low insulin –> decreased TAG synthesis

Question 27

adipose FASTED state *fat metabolism*

Answer 27

1# increased degradation of fat

high catecholamines (epinepherine and norepinepherine) –> PKA-meditaed activation of HSL –> hydrolysis of stored fat

2# increased relase of fattty acids

FA’s from hydrolysis of TAGs are released into the blood, bound to albumin and trasnported to a variety of tissues for fuel. glycerl from TAG degradation is used as gluconeogenic precursor in liver which contains glycerol kinase

3#decreased uptake of fatty acids

low LPL activity during FASTED state –> TAG of lipoproteins is not available for adipose tissue

Question 28

skeletal muscle FASTED state *General*

Answer 28

resting muscle switches from glucose to FAs as its major fuel source in fasting IN CONTRAST exercising muscle initially uses its glycogen stores as source of energy –> during intense exercise, G-6-P derived from glycogen is converted to lactate by anaerobic glycolysis –> lactate used by the liver for gluconeogenesis (Cori cycle) –> glycogen reserves are depleted –> free FA’s from adipocyte TAG hydrolysis become dominant energy source–> beta oxidation –> ACC inactivated –> low malonyl coA

Question 29

muscle FASTED state *lipid metabolism*

Answer 29

during first weeks of fasting, muscle relies on FA’s fro, TAG hydrolysis in adipose and ketone bodies for energy. after about week 3, muscle decreases use of ketone bodies (spares them for the brain) and oxidizes FAs almost exclusively. *note that acetyl coA from FA oxidation inhibits PDH and thus spare pyruvate to be converted to alanine and used in liver for gluconeogenesis (glucose-alanine cycle)

Question 30

muscle FASTED state *protein metabolism*

Answer 30

first few days of fasting > rapid breakdown of muscle protein –> provides amino acids used by liver for gluconeogenesis

Question 31

Brain in FASTING

Answer 31

early days of fasting –> brain exclusively uses glucose as a fuel –> blood glucose maintained by hepatic gluconeogenesis from precursors like amino acids from proteolysis and glycerol from lipolysis

*the netabolic changes that occur during fasting ensure that all tissues have an adequate supply of fuel molecules.

Question 32

Kidney in Long Term Fasting

Answer 32

early starvation –> kidney expresses the enzymes of gluconeogenesis including glucose-6-phosphatase –late fasting– about 50% of gluconeogenesis occurs in liver

Question 33

summary

Answer 33

Question 34

brief diagram for fasted state

Answer 34

Question 35

fed-fasted transition diagram

Answer 35