Intro

I’m going to write articles like this in the future to deconstruct the fundamentals of why people have certain symptoms.

Some goodies in the future include why people have low pulse rates, low blood pressure, low blood flow, etc…

As you will see, I am a fan of a more multi-disciplinary thinking.  The body is quite complex and there’re many causes and ways of thinking about the same condition.

The Thin-Unhealthy Paradox

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I have people fill this sheet out before a consult and two questions that I ask are if someone is tired and thin.

When I see people who are thin in the modern environment who don’t try hard to eat less, that signals a problem to me.  In this environment of abundant and amazing food at all times (including night), eating less should be a struggle.  This is especially true in the US, where the culture supports overindulgence of food.  Given the modern environment and culture, one must ask why everyone isn’t obese or at least overweight.

An early observation of mine was that the people who were thin tended to have more of certain health problems than people who were obese.  And even amongst my clients, the people who are overweight are usually in better shape in many ways than those who aren’t.

Since we know being overweight is unhealthy, this is a paradox.

Now people who are overweight surely have their health issues, but they seem to be of a different nature than the thin people.

The Most Significant Reason For Being Thin, Anxious, and Tired: Mitochondrial Dysfunction

I will give you the elevator summary here and explain the details later.

The main (but far from only) underlying cause is mitochondrial dysfunction.

When your mitochondria are not working well, you create excess superoxide and this results in oxidative stress.

Obese people also have oxidative stress, but the origins of it are different.

In thin people, mitochondrial dysfunction occurs first and this causes oxidative stress.

In obese people, consuming too many calories without expending them creates too much ATP and the body reacts by decreasing mitochondrial function.   After a while, other aspects of obesity (inflammation, etc…) itself causes mitochondrial dysfunction.

So thin people generally start out with bad mitochondria and it results in oxidative stress.  Obese people generally create bad mitochondria by having a positive energy balance, which then causes bad mitochondria and oxidative stress.

First, Let’s Define Oxidative Stress

I talk about oxidative stress a lot.  This simply means that there are too many free radicals and not enough of a capacity to quench them (Glutathione, SOD, Catalase, GPx, Etc…)

Other terms that are along the same lines: Too little negative charge or electrons in cells or a low redox potential.

A redox potential is simply the capacity to accept electrons.  A free radical is when a molecule is missing an electron (more precisely an unpaired electron).

When your body as a whole can accept more electrons (greater redox potential) and has more electrons to store, then you also have more of a capacity to give electrons and quench free radicals when they become excessive (there needs to be a balance).

Mitochondrial Dysfunction/Oxidative Stress Causes Anxiety

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Let’s get the basics down.

Oxidative stress has been implicated as a cause of depression, anxiety disorders and high anxiety levels.  (R)

One mechanism results from oxidative stress increasing HPA activation and the anxiety hormone CRH.

Oxidative stress also increases inflammation.  (R)

Oxidative stress can decrease neurotransmitters such as GABA and serotonin, which are calming.

When scientists gave a chemical to rats that cause oxidative stress, serotonin became depleted. (R)

GABA neurons are particularly susceptible to oxidative stress, and when you have high levels of oxidative stress, the neurons will break down, which results in anxiety (and increased nerve pain).  (R)

What Does Mitochondrial Dysfunction/Oxidative Stress Have To Do With Being Tired? Low ATP.

If your mitochondria are not working well, it will result in more superoxide (oxidative stress) and less ATP.

If you have less ATP, orexin will shut down more easily in response to glucose or inflammation. (R)

Orexin is the principal system that controls wakefulness and if it shuts down, our neurons shut down as well and we become tired.

We also know that inflammation also causes the suppression of orexin (causing tiredness) and can increase oxidative stress.

What Does Mitochondrial Dysfunction Have to Do With Being Thin? Low ATP.

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I think the most significant reason why people are thin has to do with low ATP, but as you will see it’s certainly not the only reason.

Thin people create too little ATP because their mitochondria are not great.

Obese people create too much ATP, which then tells the mitochondria to create less ATP because it’s not being utilized.  This happens when you eat 1000-2000 calories and then sit down at the computer for 8 years.  Too much ATP and you’re not expanding it.

The average American eats 3900 calories and is sedentary.  I’d be a fat ass if I ate this number of calories (I eat between 1/3 to 1/2 of that).

This creates too much ATP and the body has a feedback mechanism to decrease mitochondrial function to create less ATP if it’s not being expanded. It’s important to note that ATP is created no matter what you eat.

So in both thin and fat people the mitochondria are shit, but for different reasons.

One way obese people benefit from cold thermogenesis is by reducing ATP production, increasing fat burning and bettering the energy balance. (ATP is reduced by increasing UCP on the mito membranes, causing a depolarization by reducing H+ concentration).  I never did well with whole body CT possibly because my issue was different than Kruse’s, who struggled with obesity.  Once I realized this, I decided to give head CT a shot by buying a bunch of cold helmets.  See one of my cold helmets.

I will see what effect this has, but as I’m writing this, I started to get very sleepy after it.   The same thing happened when I previously took cold showers.  Could be that it’s limiting ATP production, which is leading to a suppression of orexin.  Anyway, the ICES device is waking me back up.  At this time, according to my current state of knowledge, I can only recommend whole body CT to people who struggle with being overweight. You might still benefit if you’re thin, so you can try it, but if you do try it and don’t like it, don’t stick with it.

How to Fix Your Mitochondria

In time, I will discuss the mechanisms, but for now, you can read this post on combatting fatigue.

1) Why Does Low ATP Cause Skinniness? Low insulin.

I’ve checked my insulin levels twice and both times they were lower than 2, which is extremely low.  The thin clients that checked also had low insulin.

There’s a very strong correlation between being overweight and insulin levels because insulin creates fat cells.

The question is why do people have low insulin?  And if they have low insulin, why are these people experiencing hypoglycemia as well, which usually arises from bouts of too much insulin?

To understand this, we need to understand how insulin is released.

K-ATP Channels, Insulin, and Hypoglycemia

I have four theories about why hypoglycemia occurs.

1)  Low cortisol.  The hypothalamus also controls glucose regulation most prominently by increasing cortisol (via CRHACTH).  Cortisol increases glycogen breakdown and increases blood glucose.

I think this is the most important reason.

2) High glucose levels normally increase ATP levels, which causes K-ATP channels in the pancreas to close.  This leads to a “depolarization” of the cell, which means it becomes more positively charged, which leads to calcium rushing in (and more depolarization).  This releases insulin. (R)

But if your mitochondria aren’t producing enough ATP, insulin doesn’t get secreted as well and you don’t gain weight easily.

All of my clients who are thin, have anxiety and mitochondrial problems get hypoglycemic.

An unsupported postulation about why we get hypoglycemic is that the cell membrane is polarized so much from chronically low ATP that when it gets depolarized a huge amount of insulin gets released and this causes hypoglycemia.  (You can use this to your advantage by exercising at those time periods to create good muscles with HIIT, which will also prevent hypoglycemia by creating lactate.)

There are other more supported reasons.

3) K-ATP channels also affect glucose uptake into muscle, contribute to the control of liver glucose output and appetite, and help the counter-regulatory response to hypoglycemia by increasing the release of hormones such as glucagon. (R)

The Hypothalamus (mainly the PVN) detects  glucose levels with glucose-sensing neurons.

Chronically low insulin (say from low ATP) acts in the hypothalamus to directly alter glucose sensing in hypothalamic neurons.  More specifically, it will make it so that you’d have to have lower glucose levels (i.e. hypoglycemia) to trigger a cortisol response. (R)

This is good in one way because it lowers blood glucose, but it’s bad because you become hypoglycemic more often if you don’t space your meals.

This is why I recommend thin people have frequent small meals and obese people do intermittent fasting.

The bottom line is: if you’re not producing adequate ATP, you’ll have low ATP and it will contribute to hypoglycemia in more than one way.

4) People I deal with often have low free T3.  Thyroid hormones increase the breakdown of glycogen into glucose and low T3 may contribute to hypoglycemia.

Well, just as a, BY THE WAY, hypoglycemia also causes anxiety by causing too much glutamate, mitochondrial breakdown, and oxidative stress.  So we see that mitochondrial dysfunction causes oxidative stress, which leads to hypoglycemia, which causes more mitochondrial dysfunction.

2) Circadian Dysrhythmia Causes Insulin Deficiency

Mice deficient in a circadian gene (Bmal1) had defects in insulin secretion, both at base levels and in response to glucose stimulation. These mice were highly susceptible to diabetes. (R)

All of the thin people I deal with have circadian rhythm problems, and a deficiency of BMAL1 could be one factor in this.

In mice, deficiency of BMAL1 leads to increased ROS levels in several tissues (R), which is an issue my clients deal with.

Adequate BMAL1 is needed for the production of vasopressin (R), which is something low in my clients. 

Adequate BMAL1 is needed for the production of hypoxia inducible factors (R), which is something that I’d guess would be low for my clients because they often have low EPO, which needs HIF (R).

A BMAL1 deficiency should also correlate with higher LDL cholesterol levels because BMAL1 (and CLOCK) are needed to increase LDL receptor genes, which swallow up LDL. (R)

Mice bred without BMAL1 are infertile, small in stature, age quickly, have progressive pains in joints and are more sleepy and less active (less overall locomotor activity) than normal mice. (R)

BMAL1 is lower in people with Bipolar. (R)

BMAL1 (and CLOCK) increases gene production of NAMPT, which is crucial in converting niacin (also called nicotinamide) to NAD (R), which is what puts the pedal to the metal of metabolism (R).  So less BMAL1 means slower metabolism and energy production.

NAD+ is needed for SIRT1 (R), which increases orexin 2 receptors (R), which is important for wakefulness (R).  And again, for NAD+, you need BMAL1 (and CLOCK).

Having too little BMAL1 will ruin your sleep.  Histaminergic neurons are silent during sleep, and start firing after waking.  Histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness. Deleting the Bmal1 gene from histaminergic cells results in more fragmented sleep, prolonged wake at night, shallower sleep depth (Less SWS or N3), hindered recovery sleep after sleep deprivation and impaired memory.  (R)

3) Low Oxygen (Hypoxia) Causes Low ATP and Low Insulin

I’ve been appreciating the role of low oxygen/hypoxia much more lately in the cause of people’s health issues.

Low EPO seems to be a common theme in people who have issues with mold.

When you’re hypoxic, this will cause you to have lower ATP, lower cAMP, and loss of cellular calcium oscillations, which are necessary for CRH to stimulate insulin and insulin production in general. (R)

This is one reason why people with high CRH will often have low insulin – because they’re hypoxic.

You can estimate your oxygenation by:

  • Your oxygen percentage with a “Pulse Oximeter”,
  • Your subjective circulation (ie do you have cold hands or feet?).
  • Hemoglobin count,
  • Red blood cell count,
  • Hematocrit,

Note that you can still have low oxygen if your pulse oximeter shows a high percentage.

A low RBC or hemoglobin indicates that your EPO may be low, all of which are extremely important to oxygenate the blood.  Hemoglobin holds oxygen and RBCs hold hemoglobin.  EPO produces both.

EPO is important for mood and memory independent of its effects on RBCs. (R)

I’ve been tracking my RBC, hemoglobin, and hematocrit for the past 5 years and my blood oxygen levels for a couple of years.   I subjectively realize what my circulation is like.  I used to have cold hands and feet all of the time.

Well, all of that has improved and I have the record to prove it for the RBCs, hemoglobin, and hematocrit.

The better these measures got, the healthier I felt.

Lately, my oxygen goes up to 100% and my RBC, hemoglobin and hematocrit have been higher.  My circulation is a world better and this is reflected in my elevated libido and good-temperature extremities.

My top 6 natural ways to increase EPO are:

  • Interval exercise,
  • Breath holding,
  • Astragalus  (R) – this is the best, in my experience.
  • Rhodiola/Salidroside (R),
  • Rehmannia/Catalpol (R),
  • Kidney glandular – the kidneys make EPO, so they presumably have it, and given my experiments with it, it wouldn’t be surprising.

4) High Hydrogen Sulfide and Lower Insulin

This is some food for thought.  We create hydrogen sulfide through cysteine.  The effects are lower insulin (R) and lower blood pressure (R).

It also seems that people with IBS-C produce more hydrogen sulfide (H2S) (RR2)  Makes sense because Cysteine (increases hydrogen sulfide) supplements and food give me some gas, or at least they used to.

You want to have this compound balanced.  It has a host of benefits.  It increases glutathione (R), learning (LTP), libido, protects the heart and the gut while lowering inflammation (in most tissues) (R), homocysteine, diabetes, asthma, etc.. (R).

While NAC and garlic seem to increase hydrogen sulfide, they increase glutathione, which combines with hydrogen sulfide to become GSSH, a harmless product. (R)

But do you see a picture forming? Low insulin, low blood pressure, and IBS-C all indicate higher hydrogen sulfide. Preliminary. Food for thought.

5) Less Vagus Nerve Stimulation Results In Lower Insulin

Vagus stimulation has anti-anxiety and anti-depressant effects.  People with anxiety very often have lower vagus activation and higher HRV.

Lower vagus activation means less insulin secretion because the vagus nerve is what connects the hypothalamus to the pancreas to tell it to release insulin. (R, R2)

6) 5HT2C Receptors, Anxiety, Low Appetite and Low Insulin

The 5HT2C receptor both shuts down appetite (R), causes depression (R), anxiety (R) and low insulin. (R)

When given an antagonist of the 5HT2C receptor, people with CFS reported less perceived fatigue (R), which might implicate this receptor in fatigue as well.

The receptor is increased by inflammation (R), and inflammation can also cause fatigue by shutting down orexin.

Thus, this receptor can explain why people are anxious, thin and tired.

Curcumin‘s anti-depressant effect may work in part via the 5HT2C receptor. (R)

Estradiol decreases these receptors in the ventral hippocampus (while increasing the 5HT2A receptors). (R)

7) Agouti-Related Protein, Anxiety and Being Thin

Agouti-related protein (AgRP) is a neuropeptide produced in the brain by NPY neurons in the arcuate nucleus in the hypothalamus. (R)

AgRP increases appetite and decreases metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators.  (R)

So you eat more and expend less energy from increased levels of AgRP.  Therefore you become fat from increased AgRP and thin from decreased levels.

AgRP is decreased after acute stress. (R)  This is a large reason why people lose weight after a very stressful period.

Interestingly, some people will gain weight following a period of stress, while others will lose weight.

There are many factors taking place, but some of the main ones in involved are cortisol, leptin, NPY, and AgRP.

People who gain weight may be more likely to have higher NPY, leptin, and cortisol, which increase in response to stress and cause appetite stimulation (NPY and cortisol) and produce more fat cells.

On the other hand, people who lose weight probably don’t have as much NPY and cortisol and may also experience a larger drop in AgRP.  A drop in AgRP from acute stress will make you thin.

Additionally, CRH and ACTH, the precursors to cortisol, both cause you to be thin and increase the stress response.

8) Low ATP Causes More AMPK Activation

Since we’re on the subject of low ATP, it would make sense to discuss AMPK.

AMPK is a protein in the body that ‘senses’ the AMP to ATP ratio.   When the ratio is high (when you have high AMP or low  ATP), genes start to produce AMPK.

AMP is the used version ATP and it needs to be recycled to become ATP again.

So when you have low ATP, the body senses this and increases AMPK to burn fat and create more fuel.

You see, obese people have too much ATP, so AMPK is not activated.  Thin people have too little ATP and AMPK is activated, which is healthy and is one of the saving graces for having shitty mitochondria.

Metformin and berberine are two drugs/supplements that cause weight loss and both are believed to accomplish this by activating AMPK.  So this is another mechanism by which mitochondrial problems/low ATP causes you to become thinner.

See how to activate AMPK.

9&10) Inflammation and Low PPARs

The cytokines TNF, IL-1bInterferon gamma (Th1 dominance) and interferon alpha are all fat busters. (R, R2)

Hence, it’s not surprising that anti-TNF therapy results in weight gain -an average of 5.5kg or 11 pounds in only 12 weeks. (R)

I’ve also spoken about the PPAR transcription factors bringing down inflammation and also causing obesity by increasing food intake, increasing the production of fat cells and increasing the size of fat cells (by increasing the uptake of fat and glucose in these cells.) (R)

How does this relate to anxiety?

Inflammatory cytokines including TNF have been shown to increase glutamate (by reducing glutamine synthetase, which converts glutamate to glutamine, leading to a build-up of glutamate concentrations.) (R)  Glutamate causes anxiety.

Cytokines such as TNF can also cause excess glutamate by reducing glutamate transporter on cells that create myelin.  Excess glutamate is directly toxic to these cells. (R)

Inflammatory cytokines also lead to nitrogen and oxygen free-radicals.  And oxidative stress is one of the leading causes of anxiety. (R)

Interferon-gamma/Th1 dominance can also cause anxiety indirectly. It induces an enzyme called IDO, which has the effect of lowering serotonin and increasing kynurenine, by activating the kynurenine pathway.

The Kynurenine pathway causes anxiety and depression by resulting in less serotonin, more oxidative stress, and too much glutamate. (R)

As you see in the picture below, Tryptophan gets used to create kynurenine instead of serotonin (5-HT). (R)

And then by-products of kynurenine (quinolinic and picolinic acids) excite neurons like glutamate (by being NMDA agonists). (R)

Low serotonin and high glutamate are the two principal causes of anxiety and cravings, which many people complain of even though they are thin.

So Kynurenine and its byproducts are probably a significant reason why people who are anxious also having cravings and trouble falling asleep…

Also, when you’ve got low serotonin, you’ll produce less melatonin, which will increase insomnia, which results in a disturbed circadian rhythm.  Hence, one reason why people with these anxiety issues has circadian issues.  This is beside the fact that anxiety itself will keep you up at night.

3-hydroxykynurenine and 3-hydroxyanthranilic acid are also free radical generators, causing oxidative stress and lipid peroxides. (R)  These will cause even more anxiety…

Figure 2(R)

11) High CRH

I’ve mentioned CRH in a few posts, especially the IBS post, why your cortisol is highthe harmful effects of stress, stress and skin problems and histamine issues.

CRH is a hormone that causes anxiety and it’s the first part of the stress response.   Cortisol is actually not directly anxiety-causing in the immediate term (long term, it messes with your neurotransmitters.  Indirectly, it increase kynurenine pathway).

I believe CRH is one of the fundamental causes of mitochondrial dysfunction by causing oxidative stress and I assume by some undiscovered mechanisms.

Anyway, CRH reduces appetite and causes anxiety.  This is another significant reason why low BMI and anxiety go together.

12) High CCK

I’ve spoken about CCK with regard to IBS, fatigue, and appetite.

CCK directly reduces appetite and causes anxiety.  Indirectly, it activates the vagus nerve, which reduces hunger as well.

If you’ve got anxiety, IBS, low pulse, low BP and low appetite, there’s a good chance your CCK is high.

13) Low NPY

NPY is an anti-anxiety hormone and is one of the big 4 that promotes hunger/weight gain.

So if you’ve got a high level of NPY, you’ll have lower anxiety, but you’ll be fatter.

Rhodiola/salidrosides increases NPY.  A good supplement to take if you’re thin, but maybe not the best idea if you’re obese.

14) Low Cortisol

Cortisol is one of the big 4 hormones that causes weight gain.

Normally, people with stress have high cortisol, which is a significant reason why stress causes obesity.  But if you’ve had this for a very long time and your system starts to break down, you’ll have low cortisol.

In these cases, people are usually very thin and have CFS.

15) Lower Cannabinoid Activation and Higher Anandamide

I’ve got a version of the gene in the CB1 receptor that causes lower cannabinoid activation.  CB1 is the receptor that THC/pot works on to cause less anxiety.

When you smoke pot your appetite goes up because CB1 both produces hunger and is anti-anxiety.

The gene I refer to isrs1049353.” I’m “TT”, which occurs in about 5% of the population.

Even one T is associated with: Lower BMI decreased hunger/increased anorexia risk (R), higher stress response/anxiety, lower BDNF, higher risk for Major Depression (dependent on low BDNF), intestinal inflammation, later onset of IBD but it’s more severe and higher adiponectin

The T allele causes you not to build a tolerance to pot as much (lack of receptor desensitization) and have fewer receptors (makes it less likely to activate).

People with T’s should theoretically do better with pot because they are less predisposed to build a tolerance to its effects.

Another gene rs324420 codes for an enzyme, FAAH, that breaks down anandamide, which is our natural chemical that activates the CB1 receptor.  AA and AC have a higher rate of anorexia. (R)  I have one A.

Indeed, anorexics have been found to have higher levels of anandamide. (R)

Having a T in the CB1 gene and an A in the anandamide gene synergistically increases anorexia risk.

16) Vagus Nerve Activation

This should actually be in the top 5…

Vagus nerve blocking helps obese people lose an average of nearly 15 percent of their excess weight. (R)

The problem is when you block your vagus nerve,  you’ll have more cognitive issues, anxiety, inflammation and gut problems.

You want to activate your vagus nerve.

Lack of vagus nerve activation may help explain some of the thin-anxious-unhealthy paradigms.

Because the vagus nerve is associated with many different functions and brain regions, preliminary research shows positive effects for a variety of conditions including various anxiety disorders, Heart disease, Intestinal barrier breakdown, OCD, Alzheimer’s disease, Memory and Mood disorders in elderly, migraines, fibromyalgia, obesity, tinnitus, Alcohol addictionAutism, Bulimia, Severe mental diseases, Multiple sclerosis and Chronic heart failure. (R)

17) Low Leptin

Leptin is a satiety hormone and one of the big 4 hormones that influence appetite and weight.

Obese people are paradoxically known to have higher leptin and thin people have lower leptin, presumably because of leptin resistance.

When you have dopamine in your amygdala, it causes anxiety.  Leptin stops dopamine activation in the amygdala.  So higher leptin may decrease anxiety in at least one way.

Animals without leptin receptors in their amygdala have higher levels of anxiety and dopamine activation because leptin can’t reduce the anxiety. (R)

Perhaps by causing leptin resistance, it’s one way that lectins can cause anxiety.

I need to look into the leptin-anxiety connection more.  May be spurious.

18) High Adrenaline

High adrenaline can explain anxious people being thin, but not necessarily the fatigue part.

Adrenaline leads to the release of fatty acids from adipose tissue. (R)

Beta 2 and 3 adrenergic receptors, which are receptors that are activated in response to adrenaline, increases fat busting (lipolysis). (R)

19) Bombesin

Bombesin stimulates gastrin release from G cells.  Gastrin is a peptide hormone that stimulates secretion of stomach acid (HCl) by the parietal cells of the stomach and aids in gut flow.  Together with cholecystokinin (CCK), it is the second major source of feedback to stop eating (R).

Bombesin reduces food intake of normal and hypothalamically obese rats and lowers body weight when given chronically. (R)

Bombesin can also cause anxiety (R).

20) Low Glutamate Decarboxylase/GAD Antibodies

If you have low glutamate decarboxylase, you might produce less insulin and you’ll also have increased glutamate.

See my post on how gluten can cause GAD antibodies.

21) Lower SIRT1/NAD+

Lower SIRT1 can explain being tired and having lower insulin.

SIRT1 is critical or mitochondrial function and energy production.  SIRT1 also increases orexin 2 receptors, which is important for wakefulness.  If you have lower SIRT1 levels you will be fatigued (R).

SIRT1  increases insulin secretion.  Lower SIRT1 would mean you should have less insulin secretion. (R)

Nicotinamide mononucleotide (NMN) and NAD+, which SIRT1 needs to be active, increase insulin release from the pancreas (R).  Lower levels of NAD+ should result in lower insulin and fatigue.

22) Quinolinic acid

Injection of quinolinic acid in the brain results in a drastic reduction in body weight decreased physical activity, increased oxidative stress and impaired mitochondrial function in rats (R).

People chronic inflammation or chronic stress have higher levels of quinolinic acid, which might be part of the reason why people in these states often weigh less.

23) Agouti-Related Protein (AgRP)

AgRP is a protein that potently promotes weight gain.

Agouti-related protein (AgRP) is a neuropeptide produced in the brain by NPY neurons in the arcuate nucleus in the hypothalamus. (R)

AgRP increases appetite and decreases metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators (R).

So you eat more and expend less energy from increased levels of AgRP.  Therefore you become fat from increased AgRP and thin from decreased levels.

AgRP is decreased after acute stress. (R)  This is a large reason why people lose weight after a very stressful period.

Interestingly, some people will gain weight following a period of stress, while others will lose weight.

There are many factors taking place, but some of the main ones in involved are cortisol, NPY, and AgRP.

People who gain weight may be more likely to have higher NPY and cortisol, which increase in response to stress and cause appetite stimulation and produce more fat cells.

On the other hand, people who lose weight probably don’t have as much NPY and cortisol and may also experience a larger drop in AgRP.  A drop in AgRP from acute stress will make you thin.

People suffering from chronic inflammation will have lower AgRP.

For various reasons (such as lectins), my clients often have elevated IL-1b in their hypothalamus.

Higher cortisol is a signal that IL-1b is elevated in the hypothalamus.

IL-1beta inhibits the release of AgRP from hypothalamic tissue (R).

The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin (R).  Ghrelin significantly increased AgRP in the presence, but not absence, of Glucocorticoids (R).

Levels of AgRP are increased during periods of fasting (R).

It has been found that AgRP stimulates the HPA axis to release ACTH, cortisol, and prolactin. It also enhances the ACTH response to IL-1-beta (R).

AgRP has been demonstrated to block (inverse agonist) MC3-R and MC4-R (R).

AgRP induces obesity by chronic antagonism of the MC4-R (R).

When activated, MC3- and MC4 receptor activation help people lose weight. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone).

Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R.

In the adrenals, AgRP blocks α-MSH-induced secretion of cortisol in mice (R).

Loss or gain of AgRP function may result in inadequate adaptive behavioral responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders (R).

Some studies suggest that inadequate signaling of AgRP during stress may result in binge eating (R).

Recent studies have shown that autophagy plays a key role in the regulation of food intake and energy balance in maintaining neuronal AgRP levels (R).

Cortisol (Glucocorticoids) increases AgRP (and NPY) gene expression in the arcuate nucleus through increasing AMPK (R).

Autophagy takes place while sleeping, so it’s important to get good sleep. An Infrared Sauna can also increase autophagy.

If you’re thin, it means you have low AgRP and you need to reduce your stress levels.

If you’re overweight, it means you have high AgRP and you need more sun.

24) POMC Neurons in the Hypothalamus

Activation of Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) suppress appetite while inhibiting them causes obesity (R).

Orexin suppresses the firing of these neurons, which causes hunger (R).

Cytokines and HPA activation (CRH) increase POMC (R) and therefore will cause weight loss in this manner.

People who have chronic inflammation and/or chronic stress will often weigh less because POMC will be elevated and activate POMC neurons.

25) Neuropeptide S (NPS)

When NPS was injected directly into the hypothalamus (LH and PVN), chicks reduced their food and water intake (R, R2).

Animal studies show that NPS suppresses anxiety and appetite, and induces wakefulness and hyperactivity, including hypersexuality, and plays a significant role in the extinction of conditioned fear (R).

It has also been shown to significantly enhance dopamine activity (in the mesolimbic pathway) (R).

People with anxiety, fatigue, lower libido might in part be from lower NPS/NPSR1.

26) 5HT2A

Activation of 5HT2A receptors causes anxiety and people with genes that had increased activation were more likely to get CFS.

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21 COMMENTS

  • John Macgregor

    Thanks again Joe – a terrific tour d’horizon.

    So what do we thin, tired people do now?

    I’m on the lectin avoidance diet. Should I add some of the above supps, such as rhodiola, astragalus, Rhemmania & kidney glandular – and stimulate the vagus nerve & fix the circadian cycle?

    1. Nattha Wannissorn

      Depending on if you are Th1 or Th2 dominance re:supplements. Vagus nerve and circadian rhythm should always be addressed.

      1. John Macgregor

        Thankyou Nattha.

        I’m Th1 dominant.

        The article mentions Astragalus, Rhodiola (salidroside), Rehmannia/catapol and Kidney glandular.

        The “how to reduce Th1 dominance” page only mentions one – Rhodiola – which “increases both Th1 and Th2”.

        So I’m assuming I’m safe with the other 3?

      2. John Macgregor

        PS: Just found Joe’s astragalus page, where he says “Astragalus is potent Th1 and immune stimulant”.

        So (for a Th1 dominant person) I guess that’s out too?

        (Astragalus is used against AI, which is puzzling. E.g. I used it to help me get rid of kidney disease.)

        Thanks again…

  • Lynn D

    Sounded as though fit the high CCK but also H sulfide (depending on why its there, wouldnt possibly B2, or Mo be helpful, or eating less thiols or…). Though recently my day pulse has been in ~65-72, usually is 53-60 or before up, 47-57.
    What else effects feeling hot and cold? whole life trouble with hot and cold weather (in evening for last 2 mths get sweaty neck but face is cold/clammy.(either take a break and walk or read or…. helps)

  • Ole

    Didnt know where to send you this so leaving it in a comment: http://neurosciencenews.com/gaba-depression-rapid-treatment-2227/

    Brand new study on new type of new drugs in development

  • Abdulrahman

    Hi Joe,

    On this subject i happen to be a specialist, primarily because i was genetically thin most of my adult life, until i studied natural medicine for a total of 16 years. I used to be 165 pounds at full adult weight, now weigh 220 pounds muscular, about 15 % body fat.

    In a nutshell, i will beg to disagree with your analysis of why thin people are in their present condition, what are the exact biological causes, and how to fix the situation:

    1- First step is to recognize that modern man has been linked through genetic testing to one Adam and Eve living only 250,000 years ago. See Natural Geographic Genome project.
    2- Since then Humans have undergone numerous genetic defects over the years which have severely degraded the original genetic quality of the human body. On the other hand, wild animals have not seen such degradation due to the natural selection laws of survival of the fittest. The “thin” and “fat” animals were either eaten or lost out to disease as compared to the more hardy genetically superior animals. The “unsexy” male animals were also shunned by the females….:) who preferred the well-built animals.
    3- Being thin [ or excessively fat] is a result of thousands of years of genetic defects in the body. Among them the most critical causing thin physique are: Defective digestive system in terms of low production of stomach acid, pepsin, and Pancreatic enzymes. Result of the many digestive defects are inability to properly absorb foods eaten, leading to many additional deficiencies in a vicious circle. The original human body is closer to the muscular Greek ideal physiques shown in statues….
    4- Second major cause of being thin as an Adult is underproduction of the major hormones: Testosterone, Human Growth Hormone, Cortisol [ you got this one right…:)], and IGF-1 which is linked to Human Growth hormone. There are numerous varieties of genetic defects causing underproduction of these growth hormones which also have a direct impact on food intake as they control hunger hormones also. no need to mention specific names.
    5- Incorrect maternal nutrition during the pregnancy, leading to underweight babies or babies with incorrect development of organs.
    In some cases, damage to the male or female sperm-eggs due to Alcohol or other chemical toxins which damage the growing fertilized egg.
    6- Incorrect human nutrition from birth to adulthood is a third major cause of being thin, some of this malnutrition is linked to poor digestion-absorption, but another cause is incorrect dietary food patterns with insufficient nutritional content in daily foods. In some countries this malnutrition is not due to choice but due to poverty and ignorance.

    There are other major causes, it’s a big subject and 99.999% of doctors are completely ignorant in this subject and cannot help anybody thin to become normal or achieving a physique that is genetically correct, muscular with correct bodyweight for height, good bone structure and low fat. . Do you really want to ask doctors about nutrition, genetics and other subjects? Its a lost case.

    Abdulrahman

  • lordilol

    also you didnt adress the causes behind mito dysfunction am i correct? except for crh , stress response.?

  • lordilol

    so the body is a big complex piece of mess.

    great.

    luckily i seem to not have mito dysfunction.

    ahh
    i will add my take
    me feeling tired:
    bad sleep,
    ejaculate too much

    and anxiety:
    situational stress.

    sleep is probably the most powerfull hack .
    on the days of super quality sleep, damn. days are very good stress wise. some guy on longecity said that a good quality sleep feels like cereblysin shot.

  • Alex

    God damn it Joe! You are constantly so spot on that it freaks me out! Really thin, really tired, normal cortisol levels despite constant stress… Still on the protocol you advised last time. 🙂 (Apart from Mg2+ calm which seemed to wake me up even more…, but I managed to figure out the sleeping issues). You could have a protocol for thin people how to put on weight, as it is really hard to balance everything out – it is never good to have too much of everything.
    Thanks for the post!

    1. Joseph M. Cohen

      🙂

  • Dylan

    Hey Joe,

    A cool thing I’ve done is to have my doc write a 6x cortisol saliva test. I think the 4x samples are lacking 2 crucial times: Midnight and 4 AM.

  • Fritz.Harber

    I am thin, tired anxious and sensitive to pain. My vitamin d3 level is 19ng/ml. I read your vitamin d3 post again + you anti fatigue post and I am confused – what supplementation would you recommend? (I have no access for sun). Thank you!

    1. Joseph M. Cohen

      Can’t be any clearer than the this as a general rec without knowing details of your case: http://selfhacked.com/blog/my-cutting-edge-protocol-to-cure-fatigue/

  • Deltrus

    This article applies so much to me! Ty.

    Have you read about methylene blue for mitochondrial health? Reviews on longecity say 1 mg 2-3 times a day is good, and it is very cheap. http://www.reddit.com/r/Nootropics/comments/2mtge6/methylene_blue_pharmacology/

    How good are the reviews for ICES for this kind of thing? Has it been giving you consistent good results? (or even better results as time goes on?)

    What do you think about caffeine/nicotine use when I have these problems? I already wait until the afternoon to take coffee/nicotine, so that they don’t amplify my already very high morning cortisol levels.

      1. Deltrus

        Oh wow, I can’t believe you actually made a post about it. I thought it was fringe enough that I didn’t have to make a search! Haha.

  • Ryan

    Do you know why weed would cause anxiety in others then? I’m super hit or miss with it

    1. Joseph M. Cohen

      THC produces anxiety

  • Joanna

    Thank you so much for this.
    A lot of eastern asians fit this profile actually, and TH2 dominant too for some reason.

    1. Joseph M. Cohen

      Thx 🙂

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