Integration of

metabolism
PMF Uncouplers Were Once Diet Pills
Acidic phenols shuttle protons across the inner
mitochondrial membrane, dissipating the PMF.

Side effects include permanent fever, sweats and

insomnia. Occasionally death.
Everything in Metabolism is Connected
Regulation of Each Pathway Follows Similar Themes

Activation/Inactivation of key enzymes.

Generally those that perform the committed steps.

Allosteric regulation linked to energy charge.

Ie. [AMP]/[ADP]/[ATP].

Coordination of opposing pathways.

Futile cycling with kinases/phosphatases.
Counter regulation. Eg. Glycolysis/Gluconeogenesis.
Key Regulators in Glucose Consumption
Phosphofructokinase 2 (PFK2).
Activates PFK1, which controls the rate of glycolysis.

Pyruvate dehydrogenase complex

Controls the rate of the citric acid cycle.

Glycogen phosphorylase
Breaks down glycogen into glucose-1-phosphate.
AMP, ADP and ATP Regulate Glycolysis, the TCA and the ETC

AMP activates PFK2, ADP activates isocitrate

dehydrogenase (ICDH). ATP inhibits both enzymes.

At low [ADP] ATP synthase slows, increasing the

[NADH] and reducing [CoQ]. Increased NADH levels
slows down the CAC cycle:
allosterically (PDH complex, ICDH, -KGDH)
mass action (ICDH, -KGDH, MDH).

Low/Limiting levels of NAD+ and FAD slows some

TCA enzymes.
Glucagon Raises [Glucose] in the Blood
Glucose is Transferred Between Organs
Key Enzymes in Glucose Production/Storage

FBPase2
Fused to PFK2. Deactivates PFK1/glycolysis.

Pyruvate Carboxylase
Gateway to gluconeogenesis. Activated by AcCoA,
deactivated by ADP.

Glycogen synthase
Extends glycogen, committed step in the conversion
of G6P -> G1P -> glycogen.
Insulin Activates Glycogen Synthase and FBPase2

X
Glycolysis and Gluconeogenesis are Co-Regulated
The Brain Controls Hunger

CCK: Cholecystokinin
GLP-1: Glucagon-like protein 1
Many Peptides Regulate Food Uptake
Generally produced
after a meal, to reduce
the feeling of hunger.

Each peptide has their

own receptor protein(s).
Multiple functions, not all
linked to food intake.
Hunger is a Low Glucose Signal
Fat cells (adipocytes) use
leptins to reduce hunger.

The signal is weaker in obesity.

Deleting the Leptin Gene Leads to Obesity
ob/ob mice are always hungry.
Fats accumulate in muscles, liver, and adipose tissue.

Several adipocyte hormones are now known.

The signalling pathways are complex.

R.L. Leibel (2008) Int. J. Obes. 32, S98.

Obesity Disrupts Many Regulatory Pathways
Our Body has Many Energy Sources
Energy Source vs. Exercise Length
Long periods of exercise require slow-release
energy sources.

Phosphocreatine

Glycogen

Fatty Acids
 Carb Loading
Extends the glycogen burning phase during
prolonged exercise.

http://www.sheknows.com/food-and-recipes/articles/1035327/spicy-skillet-chicken-spaghetti-recipe
Energy consumed = energy expended + energy stored

If more energy is consumed than expended,

weight gain occurs.

Energy expended = Basal metabolic rate + Activity

The amount of energy we require each day is not

constant.

Starvation, diet, and gut bacteria affect both nutrient

uptake and the basal metabolic rate.
Starvation Shifts the Body to New Energy Sources

Sugars are not being consumed.

The brain requires glucose for energy.

Gluconeogenesis becomes more important.

Allows conversion of simple precursors to glucose

(liver) which are then exported to blood/brain.
Muscles are an Energy Source of Last Resort
Amino acids can be converted to glucose, but
this weakens the body.
Muscle function decreases during starvation, until
eventually the heart fails.

Fat stores are a better source of nutrients.

There are far more fats in the human body than
amino acids.
Unfortunately, we cant convert fats to glucose.
AcCoA Cant be Converted to Pyruvate
The pyruvate dehydrogenase complex releases
too much energy.
Unlike with glycolysis/gluconeogenesis, no shunt
pathway exists in mammals.

Fats convert directly to AcCoA, making nutrients

for the TCA but no glucose for the brain.
Starvation Leads to New Energy Sources
The Liver Makes Ketone Bodies

A mix of acetoacetate, hydroxybutate and acetone.

Moderately acidic.

Produced from fatty acids when carbohydrates are

scarce, then excreted into the blood.
Prominent in diabetics and those on the Atkins diet.
The favoured energy source of the heart.
Acetoacetate is a Backup-Energy Source
Reduces the brains glucose use
from 120 g/day to 40 g/day.

Brain cells convert acetoacetate to

acetyl-CoA, feeding into the TCA.
Aberrant Metabolism: Type 1 Diabetes mellitus
Triggered when immune cells destroy the -
cells of the pancreas.

Insulin is no longer produced.

http://diabetes-avenue.blogspot.ca/2012/06/islet-of-langerhans.html
Insulin is Released to Start Glycogen Synthesis
Without Insulin Blood the [Glucose] Never Decreases

Adipose and muscle cells dont take up

glucose.
The liver is stuck in gluconeogenesis.
A high glucagon/insulin ratio decreases [F-2,6-BP].

This results in an uncontrolled breakdown of

fats and proteins.
Fatal.
 Insulin Injections Reverse T1 Diabetes
Insulin was the first protein to be sequenced
and the first manufactured at scale in bacteria.

http://www.hektoeninternational.org/index.php?option=com_content&view=article&id=1359&catid=76&Itemid=674
Fat in Non-Adipose Tissue May Trigger Type 2 Diabetes

Tissues become less responsive to insulin,

causing pancreatic cells to overwork and die.
A complex process, not fully understood.
Side Note: Diabetes mellitus
melltus m (feminine mellta, neuter melltum)
1.Of or pertaining to honey.
2.Sweetened with honey, honey-sweet,
honeyed.

From mel (honey)

The excess sugar in the blood is

excreted through the kidneys, making
the urine of diabetics sweet.

https://en.wiktionary.org/wiki/mellitus
http://libguides.brooklyn.cuny.edu/ancientmedicine_goyette/medieval