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Fat cell metabolism
The ultimate goal of a diet is to lose bodyfat of course so let's look at the processes
controlling that. That means examining the steps involved in mobilizing fat from fat cells and
burning them off.
First, let me elaborate on what it means to lose or "burn" bodyfat. What this means is
that the fat stored in your fat cells is removed from those cells and converted to energy elsewhere
in the body. Most tissues in the body (there are a few exceptions such as the brain) can use fatty
acids for fuel, but the main ones we are interested in are skeletal muscle and the liver. I want to
mention that even though the brain can't use fatty acids directly, it can use ketones which are
made from fatty acid metabolism in the liver.
Let's look at the mechanisms underlying the process of fat loss. Although the process can
be further subdivided, we are only interested in three major steps of fatty acid metabolism:
mobilization, transport, and oxidation (burning).
Step 1: Mobilization
The first step in burning off bodyfat is getting it out of your fat cells. You might even argue
that this is the most important step since, if you can't get it out of the fat cell, you can't burn it
off.
Recall from last chapter that bodyfat is primarily stored triglyceride, with a small amount
of water and some enzymatic and cellular machinery. Mobilizing bodyfat requires that we first
break down the stored triglyceride into three fatty acids and a molecule of glycerol. The rate
limiting step in this process is an enzyme called hormone sensitive lipase (HSL).
So what regulates HSL? Although a number of hormones such as testosterone, cortisol,
estrogen, and growth hormone have modulating effects on HSL activity (mainly increasing or
decreasing total levels of HSL in the fat cell), the only hormones that we need to be concerned
with in terms of HSL activity are insulin and the catecholamines.
The primary inactivator of HSL is the hormone insulin and it only takes very tiny
amounts (depending on insulin sensitivity) to have an effect. Even fasting insulin levels are
sufficient to inactivate HSL by nearly 50%. Small increases in insulin (from either protein or
carbohydrate intake) inactivate HSL further. Additionally, the mere presence of triglycerides in
the bloodstream (via infusion or by just eating dietary fat by itself) also inhibits HSL activity so
this isn't as simple as just blaming insulin. One way or another, any time you eat, HSL is going
to be inactivated, either by the increase in insulin from protein or carbs or the presence of fat in
the bloodstream from eating fat.
The primary hormones which activate HSL are the catecholamines: adrenaline and
noradrenaline. Adrenaline is released from the adrenal cortex, traveling through the bloodstream
to affect numerous tissues in the body. This means that blood flow to fat cells has an impact on
how much or how little adrenaline will reach fat cells. Noradrenaline is released from nerve
terminals which interact directly with the cells.
More technically, both insulin and the catecholamines affect levels of cyclical AMP (cAMP)
in the fat cell which is what really determines how active HSL is. When cAMP levels are low,
HSL activity is also low and fat breakdown is low. When cAMP levels are high, HSL activity is
high and fat breakdown increases.
Insulin lowers levels of cAMP and the catecholamines, in general, raise levels of cAMP (I'll
explain this statement in a second). The higher the level of cAMP, the more active HSL is and
the more bodyfat that gets broken down and released from the fat cell. It should be clear that,
from a fat loss standpoint, we want high levels of cAMP.
Step 2: Blood flow and transport
So imagine a situation where insulin is low and the catecholamines are high, causing stored
triglyceride to be broken down (the technical word is hydrolyzed) to glycerol and free fatty acids
(FFAs). Both enter the micro-circulation around the fat cells. The glycerol can be used for a lot of
different things, including glucose production in the liver, but we can ignore it for now. Some of the FFA will simply get stored back in the fat cell (a process called re-
esterification). What doesn't get restored may either sit in the bloodstream as a free fatty acid or
bind to albumin (a protein made in the liver). So now we have albumin-bound FFAs sitting in the
circulation surrounding the fat cell Since the FFA can't be burned there, it has to be transported
away from the fat cell; this depends on blood flow to and from the fat cell.
As with insulin sensitivity and adrenoreceptor ratios, fat depots differ in terms of blood
flow. Visceral fat, for example, has an extremely high blood flow relative to other fat depots. This
is on top of being extremely sensitive to the catecholamines, and relatively resistant to the
effects of insulin. Visceral fat is mobilized fairly easily and, because of this, it generally goes
away the fastest (especially with exercise).
Relative to visceral fat, abdominal (and probably low-back) fat has less blood flow, is less
sensitive to the fat mobilizing effects of the catecholamines, and more sensitive to insulin. This
makes it more stubborn than visceral fat. Hip and thigh fat is, by far, the worst; it has the
lowest blood flow, is the least sensitive to the catecholamines and the most sensitive to insulin.
So now we have yet another reason that stubborn fat is stubborn: poor blood flow which
makes transporting the mobilized fatty acids away more difficult. Actually, it isn't entirely true
that blood flow to stubborn fat cells is always slow. In response to a meal, blood flow to stubborn
fat increases readily; at all other times, blood flow to stubborn fat is slow. Basically, it's easier to
store calories in stubborn fat than to get it back out.
Studies show that women tend to have preferential increases in blood flow to their hips and
thighs after a meal; the old wivesí tale about fatty foods going straight to the hips turns out to be
true after all. Men tend to send more to visceral fat (which is actually easy to mobilize) and more
of it sits around in their bloodstream; this makes it easier to lose bodyfat but is one reason men
are more prone to heart attacks.
But the point is made, poor blood flow to stubborn fat cells is yet another reason dieting to
sub-average bodyfat levels is difficult. So how might we improve blood flow to and from fat cells?
Blood flow to fat cells improves during fasting and, although we can't fast completely (too much
muscle loss), we can mimic the condition with a low-carbohydrate/ketogenic diet. This fits in with
our goal of lowering insulin in the first place and turns out to have an extra advantage that I'll
discuss in a later chapter.
As it turns out, thyroid levels affect blood flow to fat cells significantly. Low thyroid (which
is common among women and, I suspect, among genetically average men) decreases blood flow to
fat cells and normal or even high thyroid levels improve it. Short of using thyroid medication (a
replacement dose of perhaps 25-100 mcg), there's not much we can do here.
However, aerobic exercise improves blood flow to fat cells in addition to burning calories, so
that's a possible solution. Some studies show that aerobic exercise can overcome the normally
low blood flow to stubborn fat. Considering their problems with lower bodyfat, this might explain
Step 3: Uptake and utilization
So now we've mobilized fatty acids into the bloodstream, bound them to albumin and
managed to get them away from the fat cell and into the general circulation. What's next?
Eventually, the albumin-bound FFA will run into a tissue (such as the liver or muscle) which can
use it for fuel. The FFA will be taken up into that tissue (apparently by a specific fatty acid
binding protein) at this time for one of a couple of fates. In both liver and muscle, the FFA can
either be re-stored as triglyceride (which is unusual under normal dieting conditions but occurs
during overfeeding) or burned for energy. We'll focus only on the latter.
To be used for energy, the FFA has to be transported into the mitochondria by an enzyme
called carnitine palmityl transferase (CPT). Incidentally, this is the idea behind carnitine
supplements; by increasing levels of CPT, you get more fat burning. While this is great in theory,
it doesn't really work in practice (if it does, the doses needed are absurdly high and expensive).
CPT activity is controlled by a few different factors, including your aerobic capacity (the more
aerobically fit you are, the more fat you burn), as well as glycogen levels.
Glycogen is simply a long carbohydrate chain stored in your muscles or liver. When
glycogen is high, CPT activity is low and fat burning is low, and vice versa. This is true for both
muscle and liver. By depleting muscle and liver glycogen, we can increase CPT activity, allowing
us to burn off the fatty acids at a faster rate. This is readily accomplished with the combination
of lowered carbohydrates and intensive training which fits in with our other goals rather nicely
anyhow.
The ultimate goal of a diet is to lose bodyfat of course so let's look at the processes
controlling that. That means examining the steps involved in mobilizing fat from fat cells and
burning them off.
First, let me elaborate on what it means to lose or "burn" bodyfat. What this means is
that the fat stored in your fat cells is removed from those cells and converted to energy elsewhere
in the body. Most tissues in the body (there are a few exceptions such as the brain) can use fatty
acids for fuel, but the main ones we are interested in are skeletal muscle and the liver. I want to
mention that even though the brain can't use fatty acids directly, it can use ketones which are
made from fatty acid metabolism in the liver.
Let's look at the mechanisms underlying the process of fat loss. Although the process can
be further subdivided, we are only interested in three major steps of fatty acid metabolism:
mobilization, transport, and oxidation (burning).
Step 1: Mobilization
The first step in burning off bodyfat is getting it out of your fat cells. You might even argue
that this is the most important step since, if you can't get it out of the fat cell, you can't burn it
off.
Recall from last chapter that bodyfat is primarily stored triglyceride, with a small amount
of water and some enzymatic and cellular machinery. Mobilizing bodyfat requires that we first
break down the stored triglyceride into three fatty acids and a molecule of glycerol. The rate
limiting step in this process is an enzyme called hormone sensitive lipase (HSL).
So what regulates HSL? Although a number of hormones such as testosterone, cortisol,
estrogen, and growth hormone have modulating effects on HSL activity (mainly increasing or
decreasing total levels of HSL in the fat cell), the only hormones that we need to be concerned
with in terms of HSL activity are insulin and the catecholamines.
The primary inactivator of HSL is the hormone insulin and it only takes very tiny
amounts (depending on insulin sensitivity) to have an effect. Even fasting insulin levels are
sufficient to inactivate HSL by nearly 50%. Small increases in insulin (from either protein or
carbohydrate intake) inactivate HSL further. Additionally, the mere presence of triglycerides in
the bloodstream (via infusion or by just eating dietary fat by itself) also inhibits HSL activity so
this isn't as simple as just blaming insulin. One way or another, any time you eat, HSL is going
to be inactivated, either by the increase in insulin from protein or carbs or the presence of fat in
the bloodstream from eating fat.
The primary hormones which activate HSL are the catecholamines: adrenaline and
noradrenaline. Adrenaline is released from the adrenal cortex, traveling through the bloodstream
to affect numerous tissues in the body. This means that blood flow to fat cells has an impact on
how much or how little adrenaline will reach fat cells. Noradrenaline is released from nerve
terminals which interact directly with the cells.
More technically, both insulin and the catecholamines affect levels of cyclical AMP (cAMP)
in the fat cell which is what really determines how active HSL is. When cAMP levels are low,
HSL activity is also low and fat breakdown is low. When cAMP levels are high, HSL activity is
high and fat breakdown increases.
Insulin lowers levels of cAMP and the catecholamines, in general, raise levels of cAMP (I'll
explain this statement in a second). The higher the level of cAMP, the more active HSL is and
the more bodyfat that gets broken down and released from the fat cell. It should be clear that,
from a fat loss standpoint, we want high levels of cAMP.
Step 2: Blood flow and transport
So imagine a situation where insulin is low and the catecholamines are high, causing stored
triglyceride to be broken down (the technical word is hydrolyzed) to glycerol and free fatty acids
(FFAs). Both enter the micro-circulation around the fat cells. The glycerol can be used for a lot of
different things, including glucose production in the liver, but we can ignore it for now. Some of the FFA will simply get stored back in the fat cell (a process called re-
esterification). What doesn't get restored may either sit in the bloodstream as a free fatty acid or
bind to albumin (a protein made in the liver). So now we have albumin-bound FFAs sitting in the
circulation surrounding the fat cell Since the FFA can't be burned there, it has to be transported
away from the fat cell; this depends on blood flow to and from the fat cell.
As with insulin sensitivity and adrenoreceptor ratios, fat depots differ in terms of blood
flow. Visceral fat, for example, has an extremely high blood flow relative to other fat depots. This
is on top of being extremely sensitive to the catecholamines, and relatively resistant to the
effects of insulin. Visceral fat is mobilized fairly easily and, because of this, it generally goes
away the fastest (especially with exercise).
Relative to visceral fat, abdominal (and probably low-back) fat has less blood flow, is less
sensitive to the fat mobilizing effects of the catecholamines, and more sensitive to insulin. This
makes it more stubborn than visceral fat. Hip and thigh fat is, by far, the worst; it has the
lowest blood flow, is the least sensitive to the catecholamines and the most sensitive to insulin.
So now we have yet another reason that stubborn fat is stubborn: poor blood flow which
makes transporting the mobilized fatty acids away more difficult. Actually, it isn't entirely true
that blood flow to stubborn fat cells is always slow. In response to a meal, blood flow to stubborn
fat increases readily; at all other times, blood flow to stubborn fat is slow. Basically, it's easier to
store calories in stubborn fat than to get it back out.
Studies show that women tend to have preferential increases in blood flow to their hips and
thighs after a meal; the old wivesí tale about fatty foods going straight to the hips turns out to be
true after all. Men tend to send more to visceral fat (which is actually easy to mobilize) and more
of it sits around in their bloodstream; this makes it easier to lose bodyfat but is one reason men
are more prone to heart attacks.
But the point is made, poor blood flow to stubborn fat cells is yet another reason dieting to
sub-average bodyfat levels is difficult. So how might we improve blood flow to and from fat cells?
Blood flow to fat cells improves during fasting and, although we can't fast completely (too much
muscle loss), we can mimic the condition with a low-carbohydrate/ketogenic diet. This fits in with
our goal of lowering insulin in the first place and turns out to have an extra advantage that I'll
discuss in a later chapter.
As it turns out, thyroid levels affect blood flow to fat cells significantly. Low thyroid (which
is common among women and, I suspect, among genetically average men) decreases blood flow to
fat cells and normal or even high thyroid levels improve it. Short of using thyroid medication (a
replacement dose of perhaps 25-100 mcg), there's not much we can do here.
However, aerobic exercise improves blood flow to fat cells in addition to burning calories, so
that's a possible solution. Some studies show that aerobic exercise can overcome the normally
low blood flow to stubborn fat. Considering their problems with lower bodyfat, this might explain
Step 3: Uptake and utilization
So now we've mobilized fatty acids into the bloodstream, bound them to albumin and
managed to get them away from the fat cell and into the general circulation. What's next?
Eventually, the albumin-bound FFA will run into a tissue (such as the liver or muscle) which can
use it for fuel. The FFA will be taken up into that tissue (apparently by a specific fatty acid
binding protein) at this time for one of a couple of fates. In both liver and muscle, the FFA can
either be re-stored as triglyceride (which is unusual under normal dieting conditions but occurs
during overfeeding) or burned for energy. We'll focus only on the latter.
To be used for energy, the FFA has to be transported into the mitochondria by an enzyme
called carnitine palmityl transferase (CPT). Incidentally, this is the idea behind carnitine
supplements; by increasing levels of CPT, you get more fat burning. While this is great in theory,
it doesn't really work in practice (if it does, the doses needed are absurdly high and expensive).
CPT activity is controlled by a few different factors, including your aerobic capacity (the more
aerobically fit you are, the more fat you burn), as well as glycogen levels.
Glycogen is simply a long carbohydrate chain stored in your muscles or liver. When
glycogen is high, CPT activity is low and fat burning is low, and vice versa. This is true for both
muscle and liver. By depleting muscle and liver glycogen, we can increase CPT activity, allowing
us to burn off the fatty acids at a faster rate. This is readily accomplished with the combination
of lowered carbohydrates and intensive training which fits in with our other goals rather nicely
anyhow.
