Inuit Genetics Show Us Why Evolution Does Not Want Us In Constant Ketosis | MWM 2.37

Inuit Genetics Show Us Why Evolution Does Not Want Us In Constant Ketosis | MWM 2.37

August 1, 2019 46 By William Morgan


Out of all the traditional diets that
humans have consumed across the globe
we would think that the diet of the Arctic,
where plant foods are scarce and the
environment imposes a high-fat
low-carbohydrate intake, we would expect
the diet of that region to produce
ketosis. And yet the inhabitants of the
Arctic have a genetic impairment in the
ability to produce ketones. How can we
explain this and what does it say about
whether ketosis is the natural state for
human beings?
Watch the lesson to find out more.
A ketogenic diet has neurological benefits.
Why do we have to eat such an enormous amount of food?
Complex science.
Clear explanations.
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Hi. I’m Dr. Chris Masterjohn of
chrismasterjohnphd.com. And you’re
watching Masterclass with Masterjohn.
We are now in our 37th in a series
of lessons on the system of energy
metabolism. And today we’re talking about
the curious case of CPT-1a deficiency
in the inhabitants of the Arctic. This is
a stunning case of evolution where the
environment of the Arctic selected for a
genetic impairment in the ability to
produce ketones. How can we explain this?
Well let’s just start by talking about
what CPT-I is and what its deficiency does.
The slide on the screen was
originally shown in lesson 22 and it
shows the role of CPT-I in transporting
fatty acids into the mitochondrion.
Fatty acids are activated to fatty acyl CoAs
in the cytosol, they come through the
outer mitochondrial membrane, through
VDAC, and into the intermembrane space.
They’re exchanged with carnitine to make
a fatty acyl carnitine by CPT-I. Fatty acyl
carnitine goes through a translocase
in the inner membrane and then it’s
converted by CPT-II back to a
fatty acyl CoA, carnitine gets freed and
returns through the translocase to pick up
the next fatty acid. We saw in that same
lesson that CPT-I is the
key regulated step in
transporting fatty acids into the
mitochondrion. In the fed state,
malonyl-CoA accumulates in response to
calories, anaplerosis, and carbohydrate
and it inhibits CPT-I,
which inhibits the transport of fatty
acids into the mitochondrion, thereby
suppressing their being burned for
energy in beta-oxidation.
CPT-I has at least three isoforms that
serve different physiological purposes.
CPT-1a is predominant in the liver and
the kidney. It’s responsible for ketogenesis
and for producing the energy needed
for gluconeogenesis and biosynthesis.
These processes are most
predominant in the liver, and the kidney
sometimes plays some role in assisting
the liver and that’s why we find CPT-1a there.
CPT-1b is a different form of the same
enzyme that’s predominant in skeletal
muscle and heart. There, CPT-1b serves
to allow fatty acids to be utilized for the
needs of those tissues rather than to
satisfy the needs of the rest of the body
as with CPT-1a in the liver and kidney.
CPT-1c predominates in the brain.
Its physiological purpose is poorly
characterized. Presumably it transports
fatty acids into the mitochondrion in
exactly the same way, but the importance
of that for physiology has less research
behind it. Of the three isoforms of CPT-I
only CPT-1a has ever generated an inborn
error of metabolism. That means that
that genetic defects that are very rare
that impair the enzyme’s ability have
only been associated with the form of
CPT-I involved in ketogenesis and the
energy for gluconeogenesis. What happens
in CPT-1a deficiency is that there’s
inadequate acetyl CoA for ketogenesis
and inadequate energy for gluconeogenesis;
remember that even though the carbons
for gluconeogenesis are coming from
amino acids, lactate, and glycerol for the
most part, the energy is produced in large
part by beta-oxidation. If you can’t make
ketones and you can’t make glucose you
wind up with a condition called
hypoketotic hypoglycemia: low ketones, low glucose.
Usually you have at least one or the other,
but if you don’t have ketones and you
don’t have glucose you’re not going
to be able to feed the brain.
The classical presentation of CPT-1a
deficiency includes hypoglycemia in
the newborn or if it manifests first in
children lethargy and seizures in
response to fasting, altered mental
status,
vomiting, diarrhea, fever, enlarged liver,
possible coma and death. Hypoketotic
hypoglycemia, hyperammonemia, and a
high ratio of free fatty acids to ketones.
The hyperammonemia occurs because
as we’ll talk about when we get to protein
metabolism we need acetyl CoA to
activate the urea cycle, which is how we
take the excess nitrogen removed from
amino acids and safely dispose of it as
urea instead of allowing it to accumulate
as toxic ammonia. And so the
deficiency of acetyl CoA leads to a
loss of urea cycle function, which means
that you can’t safely get rid of the
nitrogen and it accumulates as ammonia.
And that’s toxic to the central nervous system.
The high ratio of free fatty acids to ketones
is reflected by the fact that adipose can
release the fatty acids into the blood,
but those fatty acids will not make it into
hepatic mitochondria to generate ketones.
In its classical manifestation CPT-1a
deficiency is rare and it’s often fatal.
The mutations are usually private. What
that means by “private mutations” is we’re
talking about a specific mutation that
only occurs in a single family. When you
have a disorder that’s characterized by
private mutations, that means that
there’s almost as many individual
mutations as there are
patients, because it’s not like a genetic
polymorphism where there’s a few
different types that’s spread through
the population. It’s so fatal that it rarely
escapes the family where it originated.
It leads to a complete loss of the enzyme
activity and so it’s almost always fatal if not treated with
frequent feeding, because of the fasting
intolerance, and a high-carbohydrate diet,
because the fatty acids can’t be
efficiently made into ketones. In the Arctic
there is what’s called the Arctic variant
of CPT-1a deficiency. This is
a polymorphism known as P479L. It’s a
single mutation that not only is found beyond
the family, it is actually the normal form
of the CPT-1a gene throughout the entire Arctic.
Unlike the classical manifestation where
there’s a complete loss of enzyme activity,
there’s about 20% residual enzyme activity.
It’s normal in Arctic populations with
homozygosity, meaning getting the
defective gene from both parents, rates
of homozygosity as high as 88%. It’s
usually asymptomatic, but it causes low
ketone production and high rates of
hypoglycemia in response to fasting.
The Inuit have three times the rate of
infant mortality that you would expect
and that infant mortality correlates
with CPT-1a deficiency among
individuals and among the prevalence of
this deficiency in the communities.
So this does act as a metabolic disorder in
the Inuit because it does cause fasting
intolerance, it does cause low ketone
production,
and it does contribute to infant mortality.
Yet it’s not so severe as to cause even
symptoms let alone death in the majority of
people providing that they
aren’t exposed to fasting very often, and
it’s become the normal form of the gene.
This is stunning because it’s the only example known of
where a metabolic disorder has become a
permanent fixture in a population. In the
Greenland Inuit 54% are homozygous,
38% are heterozygous, and only 8% of the
population have the normal gene.
In the Canadian Inuit 88% are homozygous,
10% are heterozygous, and 2% have the
normal gene. This is also the normal gene
in Northeast Siberia, and it’s not found
outside the Arctic. So it’s Arctic-specific
and it’s taken over the entire Arctic.
The next reason that this is utterly
stunning is because it became normal,
the evidence says, not because of a
founder effect, for example, which is
where someone happened to move
into the Arctic who had that gene and
everyone there was born from them and
that’s how it became normal.
Rather, there was a selective sweep, which
means that this mutation existed
somewhere and the environment selected
so strongly for that as an advantage
that it just sweeped the entire population through
positive selection to become normal.
That is stunning because this is
an impairment in fat metabolism.
Why would the environment imposing a
high-fat diet on the population
positively select for an impairment in
fat metabolism as beneficial?
Take a look at this abstract. “Arctic populations live
in an environment characterized by
extreme cold and the absence of plant
foods for much of the year and are
likely to have undergone genetic
adaptations to these environmental
conditions in the time they’ve been
living their. Genome-wide selection scans
based on genotype data from native
Siberians have previously highlighted [a
particular chromosome region] containing
[particular genes] as the strongest
candidate for positive selection in that
population. However it was not possible
to determine which of the genes might be
driving the selection signal.” So they
performed an analysis here where they
found the P479L mutation that we were
just talking about and CPT-1a
a key regulator of mitochondrial
long-chain fatty acid oxidation.
“Remarkably the derived allele
is associated with hypoketotic
hypoglycemia and high infant mortality
yet occurs at high frequency in Canadian
and Greenland Inuits and was also found at 68%
frequency in our Northeastern Siberian
sample.”
Unfortunately they don’t say the
heterozygosity and homozygosity of the
Northeast Siberian sample. However 68%
frequency means that if you add up the
two genes that each person has
and you look at the percent of the total
genes that are the CPT-1a deficiency,
it’s 68 % of those.
For comparison in the Greenland Inuit that we just
looked at in the previous slide the
frequency was 73%. So a 68% frequency
means that it’s almost as normal in
Northeastern Siberia as it is
in the Greenland Inuit.
They go on: “we provide evidence of one
of the strongest selective sweeps
reported in humans. This sweep has
driven this variant to high frequency in
circum-Arctic populations within the last six
to twenty three thousand years despite
associated deleterious consequences,
possibly as a result of the selective
advantage it originally provided to
either a high-fat diet or a cold
environment.” They’re reporting this as
“one of the strongest selective sweeps
reported in humans.” That means that this
allele, which causes a metabolic disorder,
was judged by evolution to be one of the
most advantageous genes matched to an
environment ever. So let’s look at what
this is probably doing biochemically.
The Arctic variant is reduced to 20% of the
activity of the normal version of CPT-1a.
It’s also been found to be less
sensitive to malonyl CoA inhibition,
so that means that, even though it’s very
low activity all the time, when the Inuit are
in the fed state there’s not much inhibition.
So in normal CPT-1a you have high activity
in the fasting state, low activity in the fed state.
In the Arctic variant you have
this very low activity that remains
largely constant between the fed state
and the fasted state. What this should do
is it should mean that fatty acids
coming into the liver mostly do not
enter the hepatic mitochondria because
the CPT-1a is deficient. Because there’s
20% residual activity you get a slow
drip of fatty acids into the liver’s
mitochondria regardless of fasting
or feeding and what you do get is
directed into beta-oxidation. Because the
priority with beta-oxidation is to give
the liver the energy that it needs and then make
ketones, most of what does get into the
hepatic mitochondria is going to provide the
energy for gluconeogenesis. There will be
a slow leak of whatever exceeds that
amount needed to make ketones, but under
most conditions because very little is
getting in in the first place and your
number one priority is gluconeogenesis
there’s not going to be very much left
over for ketogenesis under most contexts.
Most of the fatty acids that would have
entered hepatic mitochondria instead
stay in the cytosol and they’re directed
into triglyceride synthesis. The triglycerides
leave the liver and then they’re taken up
by heart and skeletal muscle.
And the heart and skeletal muscle
can burn the fatty acids directly using
CPT-1b, which is not affected at all by
the classical metabolic disorder or the
Arctic variant. Now you can see why under
ideal conditions this could allow
someone to go through life with very
little symptoms. But you can also see why
many things could go wrong. For example
let’s say the fatty acids make triglycerides,
but there’s not enough choline to allow the
triglycerides to exit the liver. Choline
deficiency impairs triglyceride export
and causes fatty liver. In addition
oxidative stress can also impair
triglyceride export and so if there’s
inadequate antioxidant protection that
also could trap the triglycerides in the
liver, in that case the person gets fatty
liver disease and the energy does not
make it back to heart and skeletal
muscle and those tissues will starve.
If beta-oxidation is to supply energy for
gluconeogenesis that assumes that
there’s sufficient glucogenic substrates.
Perhaps in fasting or in very
low protein intake that could be
impaired. It also implies that there’s
sufficient oxidation of NADH produced by
beta-oxidation in the electron transport
chain. If there’s nutrient deficiencies,
other genetic issues, variations or
defects, or toxins or anything that would
impair the electron transport chain you
may need large amounts of NADH to shove
it into the electron transport chain to
get enough ATP and if all you get is
this slow leak of NADH that might not be
enough to make the ATP that you need for
gluconeogenesis. So this is situated
where under ideal conditions it can be
compatible with health, but it could make
a person more vulnerable to any of these
other effects producing ill health.
The normal effect of the Arctic variant
should be to take someone from a balance
between CPT-1a activity providing
ketogenesis and CPT-1b providing fatty
acid oxidation in muscle and heart to a massive
imbalance favoring CPT-1b activity.
What this means is that you largely lose the
capacity for ketogenesis, but providing
you feed the brain with glucose and you
get the fatty acids to the skeletal
muscle and heart everything is a-okay.
As we would predict, the Arctic variant
has been shown to result in a striking
lack of ketogenesis in response to fasting.
In this study they took 5 children who were
homozygous for the Arctic variant and
they subjected them to a medically
supervised 18-hour fast. On the left are
free fatty acids, on the right are ketones.
This shaded area represents the normal range
for children of their age and the symbols
and lines represent the data for the
individual children.
You can see that the free fatty acid
response to fasting was pretty much
normal. However, this is the normal range
for ketones in a 24-hour fast and this
is the data for the 5 children.
Not only did they have a strikingly less
than normal production of ketones, but
the production of ketones during the
18-hour fast is close to zero. Out of
these children, two developed symptomatic
hypoglycemia with blood glucose values
reaching 50 milligrams per deciliter in
one subject and 25 milligrams per
deciliter in the other. So although the
Arctic variant is associated with health
it produces an inability to make ketones
and a strong predisposition to
develop dangerous hypoglycemia in
response to fasting. How can we make
sense of why an environment imposing a
fat-based diet would provide incredibly
powerful selective pressure for a
genetic deficiency in the ability to
turn fat into ketones, especially when it
provides vulnerability to hypoglycemia
in response to fasting and increases
infant mortality by threefold? What I
propose is as follows: the Arctic
environment imposes perpetual ketosis on
a population that has normal ability to
produce ketones. If that person has
everything else about their situation
compatible with health then the
perpetual ketosis itself will be
compatible with health. But if that
person is forced into ketosis and they
have a genetic susceptibility to
ketoacidosis or they have other
precipitators associated with
ketoacidosis that contribute to
catabolic stress like injury, illness,
food deprivation or high workloads, then
with the right mix of stressors and
vulnerabilities that perpetual ketosis
can be transformed into clinical
ketoacidosis, which in the absence of
medical treatment, which would certainly
be the case in prehistory, would mean death.
That means that there could be a
fairly high risk of ketoacidosis in the
population without that CPT-1a
deficiency and the CPT-1a deficiency
would cause incredible protection
against ketoacidosis. For a deficiency
that has the downsides we’ve talked
about it must be the case that evolution
judged the threat of ketoacidosis far
greater than the threats posed by
fasting intolerance and increased risk
of hypoglycemia. It’s important to
realize that when we compare this
hypothesis to our own experience with
ketosis and the experience in the clinic
or in the research studies we have to
realize that we have the ability to
choose our diets. So if we don’t tolerate
veganism well we are not likely to be
vegan or stay vegan; if we don’t tolerate
ketosis well we’re not likely to stay in
ketosis. In the Arctic environment the
person who didn’t tolerate ketosis well,
because they were vulnerable to
ketoacidosis for example, wouldn’t
be able to choose otherwise and that’s
why the selective pressure would be so
strong. To sum this up, environments that
force very high-fat diets exert
extremely strong selective pressure
against ketogenesis. That means that
evolution does not want us in a constant
state of ketosis and it makes the idea
incredibly questionable that ketosis was
the normal state of our ancestors.
Certainly occasional fasting induced
ketosis, yes. But ketosis from a permanent
ketogenic diet? No. Additionally there are
many other arguments against that; for
example we know that there are starch-
specific adaptations like duplications
and salivary amylase genes in human
populations that make it clear that we
consumed starches long ago in our
prehistory. We also know that as you get
closer to the equator where we evolved
diets get higher and higher in plant
foods. Now this isn’t an argument against
the utility of ketogenic diets. What it
is is to set the context that the
ketogenic diet is a diet that uses a
biohack of our metabolism that is
designed to support fasting to achieve
specific medical or health-related goals.
To see that as a biohack, man, respect. But
we can’t look at this from the
foundational perspective that this was
the ancestral diet of humans.
It wasn’t. And evolution responded swiftly
and strongly when the environment
imposed that kind of diet as a permanent
fixture. With that said, let’s go on now
in our future lessons in this unit
to look at the ketogenic diet as an
important tool that can be used to
support health.
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Signing off, this is Chris Masterjohn of
chrismasterjohnphd.com. You’ve been
watching Masterclass with Masterjohn.
And I will see you in the next lesson.