LECTURE 26 - MIDTERM 3

Question 1

T or F, the heart, the brain and the intestine have no fuel reserves

Answer 1

True

Question 2

What are the fuel reserves of muscle, adipose tissue and liver?

Answer 2

• • liver = triacylglycerols and glycogen
• • adipose tissue = triacylglycerol
• • muscle = glycogen and protein

Question 3

Describe metabolic division of labor among major organs.

Answer 3

– each organ must be provided with fuel to meet it’s own specialized energy needs

– major fuel reserves are: triacylglycerols (adipose), protein (skeletal muscle) and glycogen (liver).

– most organs that produce a fuel, don’t use it directly

Question 4

Describe Brain metabolism and how it works.

Answer 4

– the brain stores little energy aas glycogen and relies almost entirely on circulating glucose for fuel

– brain glucose consumptions is 120g/day and accounting for some 60% of the utilization of glucose by the whole body in the resting state

– the brain is a highly aerobic organ accounting for at least 20% of total energy consumed (5.6mg glucose per 100g human brain tissue per minute), this is due to higher cognitive functions and glucose utlization in humans (evolutionary)

– has no significant fuel stores, but can adapt during fasting or starvation to use ketone bodies which come from ketoneogenesis

Question 5

What is ATP in the brain used for?

Answer 5

– used for neuronal (drives ion pumps that maintain membrane protential for nerve impulses)

– and non-neuronal cellular maintenance, as well as generation of neurotransmitters

Question 6

Describe Muscle metabolism.

Answer 6

– muscle can use many different fuels: glucose, fatty acids and ketone bodies

– energy use varies widely with activity levels:
- resting muscle uses primarily fatty acids from blood
- during exertion, muscle uses glucose from muscle glycogen, then
uses fatty acids. Muscles store 3/4 of body’s glycogen. However, it
isn’t released into blood like liver glycogen (no glucose 6-
phosphatase)

– during exertion, flux through glycolysis exceeds flux through CAC, causing pyruvate to build up, which is converted to lactate and released into blood stream. (this is where the muscle soreness/burn happens during working out) Taken up by liver, converted to glucose via gluconeogenesis in Cori cycle. Heart can also use lactate and oxidize it to CO2.

Question 7

What is the purpose of the Cori Cycle?

Answer 7

– purpose is to get lactate out of muscle cells and convert it to something that is less harmful

Question 8

Why is muscle breakdown in the body the last resort?

Answer 8

– muscle has a source of energy in protein however, breakdown is energetically wasteful and harmful

– process is minimized, except in starvation

Question 9

Describe Heart Metabolism.

Answer 9

– largest metabolic demand

– fatty acids, ketone bodies, glucose, and lactate are the primary substrates of the heart metabolism to generate ATP

– differs from skeletal muscle in 3 ways: work output is more consistent, completely aerobic tissue (high numbers of mito), few energy reserves (small amount of creatine phosphate, no glycogen or lipds)

– supply of oxygen and fuels must be continuous

– ATP required to fuel contractile function and viability

Question 10

What happens to heart metabolism during pregnancy?

Answer 10

– during pregnancy fatty acid breakdown is preferred rather than glucose because all the glucose is going to the baby

Question 11

Describe Adipose Tissue Metabolism.

Answer 11

– Adipose tissue serves three main functions: heat insulation, mechanical cushion and most importantly, a source of energy

– stored TGs can amount to 133,000 Cal in average human

Ex: The average woman with 20% body fat has about one month of energy stored as fat

– Adipocytes are designed for continuous breakdown and synthesis of TGs via activation of hormone-sensitive lipases

Question 12

Describe Liver Metabolism.

Answer 12

– primary role is to synthesize fuels for other organs:

- fatty acid synthesis
- glucose (synthesizes glucose from glycogen) via gluconeogenesis from muscle lactate or alanine, glycerol from adipose tissue or dietary amino acids not needed for protein synthesis
 - Glucose also derived from glycogen breakdown
 - Ketone bodies (a by-product of incomplete fat metabolism)

• • controls blood glucose levels via hexokinase IV (glucokinase) and liver-specific glucose transporter (GLUT-2)
    
    • Both respond to high blood glucose levels, by taking up and phosporylating glucose (for glycogen) when it is a high concentration
      - Responds to “fed” state by adding glycogen stores and to “fasting state by mobilizing glycogen”

Question 13

What is the most important metabolic organ? And what does it store?

Answer 13

Liver; stores glycogen and triacylglycerols, however doesn’t use them it stores them and moves them out

– can make glucose from amino acids however this is the last resort

– can make fatty acids, they come from stored adipose tissue and our diet

Question 14

What is the difference between Glucokinase (Hexokinase IV) and Hexokinase

Answer 14

– Hexokinase is present all throughout the body but Glucokinase is present only in the liver

– Hexokinase remains active all the time but Glucokinase is only active when more glucose is present

– Km for glucokinase is 10mM while Km for hexokinase is 0.5mM

– this means that hexokinase is saturated at all physiological concentrations of glucose –> reaches V max very quickly, has high binding affinity

– while glucokinase only reaches saturation around 50-100 mM –> needs more glucose to reach Vmax

– Lastly, Hexokinase is inhibited by its product (G-6-P) whereas glucokinase is not

Question 15

Describe regulation of Glucose metabolism in liver.

Answer 15

– HEXOKINASE: As in muscle, regulated via negative feedback glucose 6-P

– the affinity of glucose for glucokinase (hexokinase IV) is much less than its affinity for hexokinase - 50 -fold less

– And, Glucokinase (Hexokinase IV) is NOT inhibited by glucose 6-P

– the role of glucokinase is to produce glucose 6-P for glycogen synthesis (a glucose storage device, more later in the course on glycogen)

– Thus the logic is that when glucose is abundant, hexokinase is inhibited but glucokinase is not, and thus glycogen can be synthesized for storage

– the logic is “why would you continue breaking carbohydrates down if you already have so much ATP”

Question 16

Describe the role of Blood in all this.

Answer 16

– All organs are connected by the bloodstream, transporting fuels and waste, oxygen and carbon dioxide, and hormonal signals.

– Blood has its own energy needs, primarily glycolysis in erythrocytes (compose 99% of blood cells)

– Contain no mitochondria, so must use anaerobic glycolysis for all energy needs

Question 17

Describe Hormonal Regulation of Fuel Metabolism.

Answer 17

– very important to maintain blood glucose levels in a narrow range:

   -- between meeals 80mg/100 mL up to 120 mg/100 mL after a meal

– Mechanisms promote uptake of glucose into cells and tissues when glucose is high. When glucose levels fall, glucose is released from glycogen stores (liver) and gluconeogenesis takes place

– liver plays a central role as well as hormonal signals from other organs

– Types of hormones that regulate metabolism: insulin, glucagon, thyroid hormone, cortisol and epinephrine

– Most regulation occurs in order to maintain stable blood glucose concentrations for supplying fuel to the brain

Question 18

What is the most important hormone for glucose uptake?

Answer 18

• • Insulin

- - produced in pancreas

Question 19

What effects do Glucagon and Epinephrine have?

Answer 19

– they increase blood glucose levels

– glucagon produced in pancreas

– Epinephrine is produced by adrenal gland (fight or flight response)

Question 20

Describe Insulin and its function.

Answer 20

Pancrease has endocrine (secrete hormones into bloodstream to regulate blood sugar levels) and exocrine (secrete enxymes into intestinal ducts to break down the proteins, lipids, carbohydrates and nucleic acids in food) cells.

– also secretes lipases

– Endocrine cells are in Islet of Langerhans

– during high blood glucose levels, Insulin is screted by beta cells, which sense blood glucose levels by taking up and catabolizing glucose

–> all of this happens during the “fed” state

– Insulin is a signal that indicates a “fed” state

         - - take of fuel into muscle and adipose
         - - storage of fuels (lipids and glycogen)
         - - biosynthesis of macromolecules:

• • fatty acids and TG taken in liver and adipose
• • inhibition of gluconeogenesis in liver
• • glycogen synthesis of liver and muscle (in order to store away glucose)
• • uptake of a.a. into muscle, protein synthesis
• • inhibition of protein degradation

Question 21

Describe Negative Feedback control of blood glucose by pancreatic insulin and glucagon.

Answer 21

– Insulin can block glucagon and vice versa; won’t see them being released at same time

– insulin and glucagon regulate blood glucose levels via a negative feedback mechanism

– insulin is secreted by pancreatic beta cells

– glucagon which causes glycogen to assemble into glucose; glucagon is secreted by pancreatic alpha cells

– high blood glucose stimulates release of insulin –> the feedback comes from blood glucose rising

– low blood glucose stimulates release of glucagon –> feedback comes from blood glucose drop

Question 22

Define Glucagon and its purpose.

Answer 22

– Glucagon acts on the liver to stimulate the conversion of stored glycogen to glucose, which can then be released into the blood stream

– primary target is liver and increases cAMP levels

– result is to promote glycogenolysis (glycogen breakdown) and inhibit glycogen synthesis

– at low glucose levels F2, 6BP inhibits glycolysis and promotes gluconeogenesis

– inhibits pyruvate kinase (converts PEP to pyruvate), causing PEP to accumulate and pyruvate decreases, promoting gluconeogenesis

– also raises cAMP in adipose tissue, promoting TG mobilization via activation of lipase

Question 23

Describe Epinephrine and its purpose.

Answer 23

– released by adrenal medulla of the adrenal gland in response to low blood glucose levels

– in muscle, activates adenylate cyclase, raising cAMP, activating glycogenolysis and inhibiting glycogen synthesis.
Result: is increased blood flow to muscles and increased blood glucose levels

– Epinephrine induces lipolysis and TG breakdown in adipose tissue is activated

– inhibits pancreas from releasing insulin and activates glucagon secretion, which activates glucose production and released by liver

– short-lived effect for a “fight or flight” response

– Also has other effects on heart and skeletal muscle and as a neurotransmitter

Question 24

T or F, Muscle has glucagon receptors and therefore responds to glucagon where as liver has receptors for epi

Answer 24

False, Muscle has Epi receptors (but no glucagon receptors); therefore responds to Epi but not glucagon

– Liver has receptors for both epi and glucagon and responds to both

Question 25

Describe coordination of energy homeostasis.

Answer 25

– Balance ingestion and absorption of fuel with metabolism and storage of nutrients for immediate and long-term energy needs

– Two protein kinases are highly involved: AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR)

– AMPK is a Ser/Thr (when there is low ATP in cells) kinase that is activated when energy charge is low, stimulating ATP production and inhibiting ATP utilization pathways

– Stimulates glycolysis, glucose uptake by moving glucose transporters (GLUT4) to surface of cells (adipose, heart, and skeletal muscle)

Question 26

Describe AMPK and mTOR signaling pathways.

Answer 26

• • mTOR is also a Ser/THr protein kinase.
• • promotes anabolic processes – cell proliferation, protein synthesis, and lipid synthesis
• • mTOR is regulated by energy status, nutrient availability and growth factors (ie. insulin)
• • insulin binds to receptor activates PI3K, which promotes GLUT4 transport to surface and activates mTOR

Question 27

AMPK vs. mTOR

Answer 27

• • AMPK acts as an energy sensor and activates energy-producing pathways and inhibits energy utilizing pathways
• • when there’s low ATP, promotes energy-producing pathways
• • mTOR is active under nutrient-rich conditions and inactive under nutrient-poor conditions
• • insulin binds to receptor