Biochemistry Final - Regulation and Integration

What are the 3 key junction molecules of metabolism

1. Glucose-6-phosphate

2. Pyruvate

3. Acetyl CoA

What are the fates of glucose-6-phosphate

1. Glycogen synthesis

2. Glycolysis

3. PPP

4. Gluconeogenesis

What are the fates of pyruvate

Converted to:

1. Lactate

2. Alanine (transport of ammonia in muscles)

3. OAA

What are the fates of acetyl CoA

1. Cholesterol synthesis

2. Ketogenesis

3. FA synthesis

What is the role of the liver in carbohydrate metabolism

1. Glucose buffer: takes in and releases glucose into the blood

2. Converts glucose to glucose-6-phosphate for:

   1. Glycogen synthesis and breakdown

   2. Glycolysis → ATP

   3. Glycolysis → acetyl CoA synthesis

   4. PPP

   5. Gluconeogenesis

What is the role of the liver in lipid metabolism

1. Main fuel source for the liver

2. FA synthesis and packaging into LDLs

3. Breakdown of FAs into ketones

What is the role of the liver in amino acid metabolism

1. Absorbs majority of AAs via hepatic portal vein

2. Protein synthesis

3. AA catabolism

4. Urea cycle

2 fuel sources of the brain

1. Glucose

2. Ketone bodies (minimizes protein degradation when glucose is low)

Energy source of resting muscles

Fatty acids - creates acetyl CoA for CAC

Energy source for moderately active muscles

Glucose from glycogen and fatty acids

Energy source for active muscles

Lactate - glycolysis exceeds CAC so pyruvate undergoes fermentation

Muscle fuel sources during exercise

1. ATP and creatine hydrolysis

2. Anaerobic lactate fermentation

3. Anaerobic glycolysis (from muscle glycogen)

4. Aerobic oxidation from fatty acids (from adipose)

5. Aerobic oxidation from glucose (gluconeogenesis)

What fuels can the heart use?

Limited glycogen reserves

Main fuel source is fatty acids

Can also use glucose, ketones, lactate

How is lactate utilized as fuel in the heart

Converted back pyruvate in cardiac muscle cells → feeds CAC

What functions do the kidneys serve in metabolism

Contributes to:

1. Gluconeogenesis

2. Glucose excretion

3. Glucose filtration

4. Glucose reabsorption

What are the 3 functions of adipose tissue

1. Stores energy as triglycerides

2. Mobilizes FAs when fuel is needed via hormone-sensitive lipase activity

3. Releases hormones for energy state-signaling

What are Islets of Langerhans

Produce glucagon (alpha cells) and insulin (beta cells)

Function of insulin in liver

1. Stimulates glycolysis

2. Stimulates glycogen synthesis

3. Stimulates FA synthesis

Function of insulin in muscle

1. Stimulate glucose uptake via GLUT4

2. Stimulates glycogen synthesis

3. Stimulates glycolysis

Function of insulin in adipose

1. Stimulate glucose uptake via GLUT4

2. Inhibiting lipolysis

How are both glycolysis (catabolic) and glycogen synthesis (anabolic) stimulated by insulin signaling?

These processes occur at different times

First insulin signaling: you haven’t eaten in a while, low energy state, need energy now

Later: you’ve eaten a couple hours ago but insulin is still signaling → high energy state, don’t need energy now

Function of glucagon in liver

1. Stimulate glycogenolysis

2. Stimulates gluconeogenesis

3. Inhibits glycolysis

Function of glucagon in adipose

Stimulates lipolysis and fatty acid mobilization

Why does glucagon not affect muscle cells?

Muscle cells do not have glucagon receptors

Functions of epinephrine in liver

1. Stimulates glycogen breakdown

2. Stimulates gluconeogenesis

Functions of epinephrine in muscles

1. Stimulates glycogen breakdown

2. Stimulates glycolysis (need energy NOW)

Functions of epinephrine in adipose

Stimulates lipolysis and FA mobilization

What happens in hepatocytes during a fed state

1. Stimulates glycolysis

2. Stimulates FA synthesis

3. Stimulates glycogen synthesis

What happens in hepatocytes during a fasting state

1. Stimulates gluconeogenesis

2. Stimulates glycogen breakdown → releases glucose to blood

3. Stimulates protein catabolism (frees glucogenic AAs for gluconeogenesis)

What happens in myocytes during a fed state

AA synthesis and protein synthesis

What happens in adipocytes during a fed state

1. Stimulates TAG synthesis

2. Inhibits lipolysis

What happens in myocytes during a fasting state

1. Inhibits GLUT4

2. Stimulates use of FAs as fuel

3. Stimulates protein catabolism (creates carbon skeletons for gluconeogenesis and alanine for delivery of NH3 to liver)

What happens in adipocytes during a fasting state

Stimulates lipolysis

How is BGL maintained during an overnight fast

1. Mobilization of glycogen and release of glucose

2. Release of FAs from adipocytes

3. Muscles and liver shift to using FAs as fuel

2 priorities during periods of starvation

1. provide sufficient glucose to the brain

2. minimize protein degradation

General time course of starvation for glucose metabolism

1. Stage 1 (immediately after a meal): tissues utilize exogenous glucose

2. Stage 2 (4-16 hours after a meal): glycogen breakdown begins because glucagon signaling is high, gluconeogenesis begins

3. Stage 3 (16-24 hours after a meal): glycogen breakdown and gluconeogenesis

4. Stage 4 (2-24 days after a meal): gluconeogenesis slows, brain starts to rely on ketones

5. Stage 5 (24-40 days after a meal): brain is mainly using ketone bodies

How is muscle protein affected by starvation

Protein degradation is high to provide C skeletons for gluconeogenesis, but slows as time goes on

Protein degradation increases after 40 days because all other energy sources are depleted, results in death

How does AMPK act as a fuel sensor at the cellular level

AMP is a low energy molecule → activated by AMP

turns off ATP consuming (anabolic) pathways and turns on ATP generating (catabolic) pathways

Effect of AMPK in hypothalamus

Increases ghrelin → want to eat

Decreases energy expenditure

Effect of AMPK in muscle

1. Increases beta oxidation

2. increases glucose uptake

Effect of AMPK in liver

1. Decreases FA synthesis

2. Decreases gluconeogenesis

Effect of AMPK in adipose

Decreases TAG breakdown → prevents TAG recycling?

General mechanism of PPAR activation

Ligand-binding domain and DNA binding domain to activate gene transcription

What is PPAR

Intracellular receptor that regulates transcription of lipid metabolism enzymes

Acts as a LIPID SENSOR

Function of PPAR ALPHA

Increases beta oxidation and ketogenesis in liver and muscles during starvation

Function of PPAR DELTA

Increases beta oxidation and thermogenesis in muscle and adipose when fat stores are high

Function of PPAR GAMMA

Increases FA synthesis and storage in liver (low expression levels)

Increases insulin sensitivity in muscles (low expression levels)

Increases fat uptake and storage, adipocyte differentiation and survival of adipocytes

Role of UCP/thermogenin in fat metabolism

Uncoupling the proton gradient in the ETC prevents ATP synthesis and allows for increased beta oxidation

Role of the arcuate nucleus of the hypothalamus in energy metabolism

Acts as a regulator of energy balance by releasing hunger and feeding signals

What are adipokines

Peptide hormones that signal fat reserve levels to the hypothalamus

Produce changes in metabolism and feeding behaviors

Where are adipokines produced

Adipose tissue

How does leptin maintain levels of fat reserves

Signals the hypothalamus to suppress appetite

Signals release of alpha-MSH and inhibits NPY

Promotes energy expenditure by increasing BP and HR

Where is leptin released

Adipose tissue (it is an adipokine)

Where does leptin act

Hypothalamus

What is alpha-MSH

Neuronal signal to eat less

Where is alpha-MSH and NPY released from

Hypothalamus

What is NPY

Neuronal signal to eat more

What are anorexigenic neurons

appetite-suppressing

What are orexinergic neurons

appetite stimulating

Consequences of being leptin deficient

Obesity → no signal that fat reserves are there

How do leptin injections act to decrease obesity IN MICE

In leptin deficiency the receptors are there, they just don’t produce it

Injecting leptin restores signaling

Why do leptin injections not treat obesity in HUMANS

Obesity in humans is caused by leptin resistance

What are parabiosis experiments

You suture 2 genetically different mice together so they exchange blood

What is adiponectin

Normally present in high levels in blood

Activates AMPK to affect metabolism of fatty acids and carbohydrates

What happens in the absence of adiponectin

Insulin insensitivity and poor glucose tolerance (Similar to type 2 diabetes)

Where is ghrelin produced

stomach lining

What does PYY signal

signals satiety to the hypothalamus

inhibits NPY

Where is PYY produced

small intestine and colon

How does ghrelin affect NPY

activates it

What are incretines

peptide hormones produced by the gut after a meal

includes GLP-1

Effects of GLP-1

1. slowed gastric emptying and motility

2. increased insulin signaling

3. increased insulin sensitivity

4. decreased glucagon signaling

5. decreased gluconeogenesis

6. increased glucose uptake in muscles