Biochemistry Module 4: Regulation of Fuel metabolism

What are the 4 main tissues that partake in fuel metabolism

Liver, adipose, muscle, and brain

What are the regulatory systems for fuel metabolism

Hormones and nervous system

What are the factors that dictate the availability of substrates

Uptake mechanisms and metabolic conditions

What are the three main hormones that act as regulators of metabolism

Insulin glucagon, epinephrine

What are two hormones that additionally modulate metabolism in excess

Glucocorticoids and growth hormone

What are the metabolic processes inhibited by insulin and stimulated by glucagon

Glycogenolysis, gluconeogenesis, ketogenesis, lipolysis

What cells in the body are responsible for insulin secretion

Pancreatic Beta cells

What is required for insulin release

ATP from glycolysis

What occurs in the pancreatic B cell that leads to secretion of insulin

ATP binds and closes K+ channels leading to depolarization, calcium enters and facilitates insulin release

What drugs block the potassium channels in pancreatic beta cells

Sulfonylureas

What glucose uptake transporter is present in the pancreas

GLUT 2

What are the features of GLUT 2

High capacity and low affinity for glucose (entry of glucose only occurs at high concentrations)

What enzyme is present in pancreatic beta cells that starts glycolysis

Glucokinase

What are the features of glucokinase

High capacity and low affinity for glucose (only active when glucose concentrations are high)

Insulin has a variety of effects after binding to the RTK on the cell, how are these classified

By speed of response (fast or slow)

What are inducible products of slow insulin responses in cells

Glucokinase, liver pyruvate kinase, G6PDH, acetyl CoA decarboxylase, fatty acid snythase

What is a primary fast response to insulin on cells of adipose tissue and muscle

Incorporation of GLUT 4 transporters into the cell membrane for glucose uptake

How does mobilization of GLUT 4 occur

IR autophosphorylation, IRS phosphorylation, cascade of phosphorylation including the components of trafficking machinery to bring receptor to surface

How is termination of insulin signalling completed

Tyrosine phosphatases and serine/threonin phosphatases with dephosphorylate the cell signaling machinery

What are the stimuli for glucagon secretion

Low glucose/insulin, high epinephrine, protein rich/low carb diets

What receptor type does glucagon act on and what is the second messenger system

GPCR through Gs (cAMP and PKA)

Activation of PKA in glucagon signaling has what general effect

Phosphorylation of regulatory enzymes (glycogen synthase and phosphorylase kinase)

What receptor type does norepinephrine act on in muscle and adipose tissue and what is the general metabolic effect

B-adrenergic receptors and the effect is very similar to that of glucagon

How does insulin regulate glycolysis/gluconeogenesis in the liver

Dephosphorylation of PFK2 allows for the formation of F26BP which will stimulate PFK1 in glycolysis. F26BP also blocks gluconeogenesis by inhibiting F16BPhosphatase

In the fed state, what is glucose availability in the liver

High

What is the source of glucose entry into the liver in the fed state

GLUT 2

What is the enzyme responsible for phosphorylation of glucose in the liver

Glucokinase

What are the effects of metabolism of glycogen in the liver during the fed state

Increase in synthesis due to dephosphorylation and increased G6P, deactivation of degradation pathway via dephosphorylation of phosphorylase kinase

What are the effects of glycolysis in the liver during the fed state

Dephosphorylation of PFK2, production of F26BP activates PFK1, and pyruvate kinase is dephosphorylated leading to drive in glycolysis

What is the effect of the fed state in the liver on the pentose phosphate pathway

Increased availability of G6P leads to more NADPH production adutilization in fat synthesis (G6PDH is insulin induced)

What is the effect of the fed state in the liver on pyruvate dehydrogenase

Dephosphorylation of PDH due to an inactive PDH kinase leads to further transformation of pyruvate to acetyl CoA

What is the effect of the fed state in the liver on the TCA cycle

Initially active, but the accumulation of ATP and NADH will eventually inhibit IDH allowing citrate to accumulate and favor fat synthesis due

What is the effect of the fed state in the liver on fatty acid synthesis

Citrate more readily cleaved to acetyl coa, acetyl coa carboxylase is activated, increase in NADPH from PPP and malic enzyme drives forward fatty acid synthase, glycerol 3 P more readily converted from DHAP, and increased lipoprotein availability for export

What is the effect of the fed state in the liver on gluconeogenesis

Pyruvate carboxylase is inactivated as well as F16BPhosphatase is inactivated

What is the effect of the fed state in the liver on amino acid metabolism

Increase in protein synthesis (especially apolipoproteins) as excess amino acids undergo transamination and deamination for synthesis and urea cycle elimination

What is the availability of glucose for adipose tissue in the fed state

High

What is the mechanism of glucose entry into adipocytes

GLUT 4 (insulin dependent)

What is the glucose phosphorylation enzyme in adipose tissue

Hexokinase

What is the effect of the fed state in adipose tissue on glycogen metabolism

There are small deposits of glycogen so the fed state doesn't really change things

What is the effect of the fed state in adipose tissue on glycolysis

Increased availability of glucose and insulin actions stimulate glycolysis

What is the effect of the fed state in adipose tissue on pyruvate dehydrogenase and the Krebs cycle

The two processes are active for basal energy production (glycerol 3P synthesis)

Is gluconeogenesis a process that can be performed in adipocytes

No

What is the effect of the fed state in adipocytes on the PPP

Relatively increases activity by most of the fatty acids for TAG synthesis will come from the diet (not the same need for NADPH as the liver production)

What is the effect of the fed state in adipocytes on lipid metabolism

LPL in capillaries is stimulated to degrade TAGs in lipoproteins, increased entry of fatty acids into the cell, formation of TAGs using glycerol 3P is increased, inactivation (dephosphorylation) of HSL

What is glucose availability in the fed state for muscle tissue

High

What is the mechanism of glucose uptake in muscle

GLUT 4 (insulin dependent)

What is the glucose phosphorylating enzyme in muscle cells

Hexokinase

What is the effect of the fed state in muscle on glycogen metabolism

Glycogen synthesis occurs through dephosphorylation of glycogen synthase and glycogenolysis is halted

What is the effect of the fed state in muscle on glycolysis/PDH/Krebs cycle

Activation to provide the energy that the muscle needs

What is the effect of the fed state in muscle on lipid metabolism

There aren't a lot of fatty acids or ketones in muscle at this stage as glucose is the primary source of energy

What is the effect of the fed state in muscle on amino acid metabolism

Increase in protein synthesis and regulation of BCAA degradation for purposes of protein synthesis

What is the availability of glucose in the brain during the fed state

High

What is the glucose uptake mechanism in the brain

GLUT 1 and GLUT 3

What is the glucose phosphorylating enzyme in the brain

Hexokinase

What is the effect of the fed state in the brain on glycogen metabolism

There isn't a whole lot of glycogen but synthesis is unregulated and degradation is downregulated

What is the effect of the fed state in the brain on glycolysis/PDH/Krebs cycle/OXPHOS

Increase activity to produce the high energy demand of the tissue (brain utilizes 20% of the body oxygen)

What is the effect of the fed state in the brain on lipid metabolism

Mechanisms are not very active and fatty acids uptake is limited due to availability of glucose

What is the effect of the fed state in the brain on amino acid metabolism

Uptake mechanisms are unregulated for the continued synthesis of neurotransmitters

What is the order of fuel sources from greatest to least in terms of energy production during the fasting state

Fat, Protein, glycogen

After glycogen stores are depleted, how are glucose levels to the tissues maintained

Gluconeogenesis

What are the 3 carbon precursors that can be used during gluconeogenesis

Amino acid carbon backbones, glycerol, lactate

During the fasting state, which hormones will take dominance

Glucagon and norepinephrine (counterregulatory hormone to insulin)

As glucagon signaling progresses, what are the intended effects

Maintain normal blood glucose, avoid the use of glucose in the cells

How does glucagon facilitate maintenance of blood glucose

Increase in glycogen degradation and gluconeogenesis in the liver

How does glucagon induce tissues to avoid the use of glucose

Activating lipolysis and use of fatty acids in tissues as an energy store

What happens when glycogen deposit is in the liver are exhausted

Fatty acids are converted into ketones to preserve glucose and the brain will eventually switch to ketones as its energy source to space glucose and amino acids

What is the glucose availability for the liver in the fasting state

Medium to low

Is glucose phosphorylation or entry occurring in the liver during the fasting state

No

What is the effect of the fasting state in the liver on glycogen metabolism

Phosphorylation of enzymes will activate glycogenolysis and inhibit glycogenesis

What is the effect of the fasting state in the liver on glycolysis

Decrease the PFK2 activity which will decrease PFK1 activity as well as phosphorylation of pyruvate kinase all lead to reduced glycolysis

What is the effect of the fasting state in the liver on pyruvate dehydrogenase

Activation of PDH kinase will inhibit PDH with phosphorylation saving pyruvate for glucose synthesis

What is the effect of the fasting state in the liver on the Krebs cycle

Inactivation as OAA is used for gluconeogenesis and the abundant NADH inhibits IDH

What is the effect of the fasting state in the liver on gluconeogenesis

High availability of lactate, glycerol, and amino acid skeletons will help activate the enzymes necessary to drive gluconeogenesis forwards. (Pyruvate carboxylase is active and PEPCK is induced by glucagon. Inhibition of glycolysis and NADH in the cytosol drives the reaction forwards

What is the effect of the fasting state in the liver on glucose 6 phosphatase activity

Increased activity to release glucose from the liver (gluconeogenesis or glycogenolysis)

What is the effect of the fasting state in the liver on the PPP

Generally inactivates it as we want to preserve glucose use

What is the effect of the fasting state state in the liver on lipid metabolism

Decreased ACC activity and decreased Malonyl CoA production, but increased B-oxidation to mobilize acetyl CoA for use in ketogenesis

What is the availability of glucose in adipocytes during the fasting state

Medium to low

Is glucose phosphorylation or uptake occurring in adipocytes during the fasting state

No

Is there glycogen metabolism occurring in adipocytes during the fasting state

No

What is the effect of the fasting state in adipocytes on glycolysis

Since there is no glucose uptake, glycolysis is inactivated. This will also lead to decreased synthesis of glycerol-3-P

What is the effect of the fasting state in adipocytes on the Krebs cycle

Some activity is seen for basal energy production from acetyl CoA made during B-oxidation

What is the effect of the fasting state in adipocytes on the PPP

Inactivation as glucose is low

What is the effect of the fasting state in adipocytes on lipid metabolism

Phosphorylation of HSL activates lipolysis and mobilization of fatty acids

What is glucose availability in muscle during the fasting state

Medium to low

Does glucose phosphorylation and uptake occurring in muscle during the fasting state

No

What is the effect of the fasting state in muscle on glycogen metabolism

Glycogen synthesis is decreased but content is unaltered as glycogen is mainly used during bouts of exercise

What is the effect of the fasting state in muscle on glycolysis

No glucose availability decreases glycolysis

What is the effect of the fasting state in muscle on the Krebs cycle

Continually active to provide the energy from acetyl CoA derived from fat metabolism

What is the effect of the fasting state in muscle on lipid metabolism

Increase in fatty acid oxidation and ketone metabolism

What is the effect of the fasting state in muscle on amino acid metabolism

Proteolysis is active to provide carbon backbones for the liver and is generally stimulated by cortisol

What is the availability of glucose during the fasting state for the brain

Medium to low

Can glucose be uptaken into the brain during the fasting state

Yes, GLUT 1 and 3 are insulin independent and high affinity for glucose

What is the effect of the fasting state in the brain on glycogen metabolism

Glycogen deposits are decreased, but this is not the main mechanism for making energy

What is the effect of the fasting state in the brain on glycolysis/PDH/Krebs cycle/OXPHOS

All active due to the uptake of glucose and the fact that glucose is the preferred energy source in the brain

What is the effect of the fasting state in the brain on lipid metabolism

Use of fatty acids is typically restrained to astrocytes, but neuronal ketone use increases to spare the amino acid metabolism to reduce use in gluconeogenesis

What is the primary way that fuel is metabolized in RBCs and why

Glycolysis as RBCs dont have mitochondria (no PDH - no acetyl CoA, no TCA, no ETC, no B-oxidation, no ketones)

How is glucose take up into RBCs

GLUT 1

What is the final product of glycolysis in RBCs and why

Lactate instead of pyruvate as the RBC needs to regenerate NAD+

What glucose hungry pathway is used by RBCs to help prevent oxidative damage

PPP

What is the effect of conversion of 1,3 BPG to 2,3 BPG in RBCs

Helping the conversion of the hemoglobin to release oxygen