Lecture 27: Midterm 3

Question 1

T or F, in unicellular organisms such as yeast, metabolic phenotypes switches dependent on nutrient availability

Answer 1

True; yeast cells, like most single-celled organisms, can adapt to changes in nutrient availability

Question 2

Describe the innate control system that unicellular organisms such as yeast have.

Answer 2

– have innate control system that sense the available nutrient supply and initiates an appropriate metabolic response

– if nutrients are abundant, cells will take up fuels and metabolize glucose via glycolysis, a rapid but inefficient process aka proliferative metabolism

– if nutrients are scare, cells use oxidative metabolism to produce ATP – oxygen is used to make energy from carbohydrates (sugar)

– during increase of glucose levels, the yeast synthesizes additional glucose transporters to bring glucose into the cell as well as additional enzymes that metabolize

– if nutrients are abundant, cells use anaerobic glycolysis. Inefficient at producing ATP, but also produces building blocks for biomass

Question 3

T or F, in mammals, cell proliferation causes metabolic switch

Answer 3

– True

Question 4

Describe how growth in multicellular organisms is dependent on growth factors.

Answer 4

– Nutrients are typically always abundant in multicellular organisms via blood stream

– thus growth in multicellular organisms is dependent on growth factors (hormones) to switch from a quiescent to proliferative state

– non-dividing cells use oxidative metabolism (aerobic glycolysis + oxidative phosphorylation) and proliferating cells use anaerobic glycolysis

——-> upon stimulation by growth factors (such as insulin), differentiated cells switch to faster anaerobic glycolysis

Question 5

Describe the Warburg Effect.

Answer 5

– 1925

– Otto Warburg showed that cancer cells produce ATP primarily from glycolysis, as opposed tot he more efficient oxidative phosphorylation pathway

Question 6

Describe how oxygen in tissue dictates how glucose is utilized in normal cells.

Answer 6

– High oxygen: pyruvate enters citric acid cycle/oxidative phosphorylation which yields around 36 mols of ATP

– Low oxygen: pyruvate fermented to lactate yields 2 mols of ATP

Question 7

What do cancer cells depend on for growth?

Answer 7

– Cancer cells are not dependent on growth factor signals,

– so they undergo the rapid but inefficient process of proliferative metabolism.

– Cancer cells will metabolize glucose via aerobic glycolysis and lactic acid fermentation, –> ~4 mols of ATP, aka Warburg effect.

Question 8

What is the difference between unicellular vs. multicellular organisms in the metabolic phenotype switches?

Answer 8

• • Unicellular:
    
    • • if nutrients are scare, cells use oxidative metabolism to produce ATP
    • • if nutrients are abundant, cells use anaerobic glycolysis. Inefficient at producing ATP, but also produces building blocks for biomass.

– Multicellular:

  -- in normal cells, nutrition is not an issue. Thus, growth in multicellular organisms is dependent on growth factors (hormones) to switch from a quiescent to proliferative state

Question 8

What is the difference between unicellular vs. multicellular organisms in the metabolic phenotype switches?

Answer 8

• • Unicellular:
    
    • • if nutrients are scarce, cells use oxidative metabolism to produce ATP
    • • if nutrients are abundant, cells use anaerobic glycolysis. Inefficient at producing ATP, but also produces building blocks for biomass.

– Multicellular:

  - - in normal cells, nutrition is not an issue. Thus, growth in multicellular organisms is dependent on growth factors (hormones) to switch from a quiescent to proliferative state
  - - in cancer cells, genetic mutations can affect components of the growth factor signaling pathways that control proliferation

Question 9

How does the brain coordinate whole-body energy homeostasis?

Answer 9

– brain receives info about type and quantity of energy being consumed, fuels already present in blood and storage reserves

– fuel and hormonal signals converge in arcuate nucleus of hypothalamus, where appetite is controlled

Question 10

What are regulators of food intake?

Answer 10

– insulin and leptin: inhibit food intake

– ghrelin and adiponectin: promote food intake

• • they act on specific receptors in arcuate nucleus to initiate signaling pathways that act on AMPK and mTOR
  • —> AMPK is activated by ghrelin and diponectin in response to low levels of glucose, AA, and FFA, promoting food intake
  —> Leptin is released by adipocytes in response to sufficient fat stores and acts on arcuate nucleus receptors to inhibit food intake

Question 11

Describe how leptin as a negative regulator of food intake.

Answer 11

– Leptin is encoded by OB gene (obese). Leptin is released by adipocytes

– Leptin receptor is encoded by DB gene and mice with two defective versions (db/db) are also obese

– Leptin seems to function as a “lipostat” and when defective causes mice to overeat, as they don’t indicate that they have sufficient fat stores

– obese humans generally DO have sufficient leptin production. Possible that they are unresponsive to leptin signaling pathways

Question 12

Describe the mechanism of the Ghrelin hormone.

Answer 12

– Ghrelin is produced by cells lining the stomach

– hunger-stimulating signal

– increases production before meals and decrease after

– acts on arcuate nucleus by activating AMPK

– Adiponectin is produced by adipocytes, though seems to be at lower concentrations in obese individuals and those with Type II diabetes

– Stimulates food intake by binding receptors in arcuate nucleus and stimulating food intake by activating AMPK

Question 13

Describe the response to High Blood Glucose
: normal feeding cycle

Answer 13

– Blood glucose levels rises after a carbohydrate-containing meal. Insulin is screted by pancreas, glucagon secretion is suppressed

– Glucose is taken up by liver, made into glycogen and fatty acids (extra glucose roaming around is removed from circulation and is stored in liver)

– fatty acids are transported to adipose tissue in VLDLs. They are stored as TGs

– Glucose is taken up by insulin-dependent transport into muscle and made into glycogen for storage. Muscles can go through glycolysis (glucose can be converted to lactate and can undergo lactic acid fermentation)

– Fatty acids are used by heart for energy –> beta-oxidation (from VLDL which carry FA to adipose and heart)

– Glucose is used by brain for energy via glycolysis and oxidative phosphorylation –> brain will always be fed first

Question 14

Why is glucose even stored as fatty acids?

Answer 14

– bc there is limited space for glycogen and its’ fairly large (alpha 1-4 to alpha 1-6 bond)

– why not just glycogen

Question 15

What is the key signaling molecule for carbohydrate metabolism and lipid biosynthesis?

Answer 15

– Acetyl CoA

– glucose is made into acetyl-CoA

Question 16

What is the response to Low Blood Glucose?

Answer 16

– Blood glucose levels fall several hours after a meal

– insulin secretion (beta cells) is reduced and glucagon secretion increased (alpha cells)

– Glycogen is mobilized by the liver activating glycogen phosphorylase 9catalyzes the rate-limiting step in glycogenolysis); Fatty acids broken down by beta-oxidation

TGs are broken down in adipose tissue, generating FA and glycerol

– FA are used by muscle for energy (Beta oxidation) and create ketone bodies

– Fatty acids are used by heart for energy (beta oxidation)

– Glucose is used by brain for energy vis glycolysis and oxidative phosphorylation. Lack of insulin reduces use of glucose by muscle, liver and adipose tissue, leaving it for brain

Question 17

During low blood sugar why are fatty acids turned into ketone bodies rather than acetyl CoA?

Answer 17

– Might have too much Acetyl - CoA and they need to be turned into ketone bodies

– also have low glucose levels and can’t enter CAC and don’t have much oxaloacetate, meaning it can’t form citrate

Question 18

What are the 3 molecules that break down TGs?

Answer 18

– TGs –> diaglycerides (ATGL)

– Diaglycerides –> monoglycerides (HSL)

– Monoglycerides –> fatty acids (MGL)

Question 19

T or F, any glucose we have roaming around will go directly to brain

Answer 19

True, glucose is coming from glycogen stores also getting glucose from glycerol

Question 20

How do fats know to be broken down?

Answer 20

– by receiving hormone signaling

Question 21

What happens during starvation?

Answer 21

– Glycogen stores are exhuasted after 24 hours –> carbohydrate metabolism is long gone; haven’t eaten anything in 24 hours or more

– Blood glucose levels need to be maintained at 4mM, so other files are used (fats)

– energy stored in TG is the highest this where we have highest amount of energy

– However, TGs, are broken down into acetyl-CoA, require oxaloacetate through CAC. Needs to be replenished via pyruvate carboxylase reaction (anaplerotic), but this comes from carbo catabolism, flux through cycle is reduced (acetyl CoA will then go to ketogenesis –> has no choice, no we have ketone bodies)

– instead, glycerol is used from lipolysis (still not enough), so metabolites from protein catabolism are used, but this wastes muscle and weakens the person, but this still happens during 1st few days of starvation

Question 22

What is the response to starvation: lack of food for many days?

Answer 22

– amino acids from protein breakdown are used by liver in gluconeogenesis

• • FA from adipose tissue are made into ketone bodies (go right to heart and brain; whatever liver makes isn’t being used rather it’s exported) because of excess acetyl-CoA
• • muscles using FA to make ketone bodies for energy and proteins are broken down
• • ketone bodies used fro fuel by the heart and brain:
    
    • -> after fasting for 3 days, the brain gets 30% of its energy from ketone bodies
• –> After 4 days, this goes up to 75% sparing muscle –> brain uses both ketone bodies and broken down protein

Question 23

What is type 1 Diabetes?

Answer 23

– autoimmune disease because the body’s immune system mistakes beta cells as foreign and attacks them preventing insulin from being released

– destruction of beta cells results in loss of insulin production by the pnacreass

– treated by administration of insulin with a meal

– people with Type 1 have it for the rest of their lives

– no insulin is being secrete; have all of this glucose roaming around the cell and can’t be let inside cell

Question 24

What is Type 2 Diabetes? What are the twp hypotheses?

Answer 24

– Insulin production is often normal, but cells don’t respond correctly

– Two Hypotheses:

 ---> Lipid overload: (eat too many fats in their diets) fuel intake exceeds storage capacity of adipose tissue, accumulates on other tissues and prevents insulin signaling pathway that translocates GLUT4 --> doesn't recognize insulin hormone anymore

• —–> Inflammation: when adipose tissue increases in size, it secretes inflammatory cytokines which bind peripheral tissues and inhibit insulin signaling
  - when ur eating more fats its not like ur fat cells double, instead they just get bigger

– keep in mind that insulin is being released but something is wrong w/ the signaling bc there’s so much insulin around that the receptor is desensitized

– also note that both hypothesis have to do w/ disregulation

Question 25

What are the metabolic abnormalities associated with diabetes?

Answer 25

– lack of insulin or nonresponse results in failure of tissues, muscle, and adipose to take up glucose from blood –> FFA transported w/ serum albumin

– glucose accumulates in blood and tissues are starved of fuel

– liver increases gluconeogenesis (low insulin/glucagon ratio) from the degradation of muscle proteins.

– TG reserves are mobilized in response to low insulin/glucagon ratio

– FA oxidation is increased and produces loss of acetyl-CoA

– Oxaloacetate limitation may inhibit flucxthrough CAC –> short in supply is related to too many ketone bodies

– Acceleration of ketone body formation and presence in the blood, results in lowering of blood pH (ketoacidosis)

– High ketone bodies –> insulin deficiency (hyperglycemia) –> prevents glucose absorption –> inhibition of oxaloacetate production

Question 26

What are some of the physical symptoms and long-term complications of Diabetes?

Answer 26

– kidneys can’t absorb glucose above 10mM, so glucose is excreted in urine

– Glucose excretion creates osmotic load, large amounts of water are excreted

– signs of diabetes often include excessive thirst and frequent urination, as well as breakdown of fat and protein (weight loss).

– Type II diabetes can often be controlled with exercise and dietary restriction of carbs. Type II diabetes is reversible with diet and exercise

– Treatment for Type I usually necessitates injection of insulin in the subcutaneous tissue or insulin pumps

– Left untreated, high blood glucose levels can cause complications