A First Principles Approach To Obesity/Anorexia: The Big 4 Hormones

Gut hormones (compressed)
Negative=inhibits appetite….http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744050/figure/F1/

This is an 8 part series that will take a first principles approach to the underlying cause of obesity and anorexia.  First, we must see what the causes of obesity or anorexia before we see the best ways to modulate it.

The Basics

Your weight is solely determined by how much energy you consume vs how much you expand (via metabolic rate, exercise, etc..).  This is the law of thermodynamics.

Your percentage of muscle vs fat is determined by how many of those calories go to build muscle and how much get stored as fat and also how much fat you burn for energy vs how much muscle you burn for energy.

Your biology (hormones, etc…) will determine your metabolic rate, energy efficiency, your hunger levels and the calories that go into fat or muscle and the calories that are broken down from fat and muscle. It’s these factors that you can theoretically change.  This is what this series will focus on.

1) Leptin


See my comprehensive post on leptin.

Leptin causes weight loss.

Leptin is one of the big 4 hormones that determine weight.

Leptin is synthesized in fat tissue and receptors are found in the hypothalamus, the cerebral cortex and the hippocampus (R).

Leptin acts as a signal to the brain to inhibit food intake and enable the storage of surplus calories in fat cells. (R)

It simultaneously protects non-fat tissue from toxic effects of fat overload.  (R)

Increased leptin is associated with higher body fat mass, a larger size of individual fat cells, and the act of overeating/hunger. (R)

In rodents, leptin increases usage of  brown fat for energy. (R)

Leptin administered to animals promotes weight loss and satiation, but in obese human, it does not promote significant weight loss . (R)

Obese humans have high levels of leptin, even though leptin is supposed to cause satiety, which suggests that leptin resistance causes human obesity. (R)

This seeming contradiction can be explained by a mutation of a leptin receptor, either as a result of lectins (leptin is completely different from lectins) (R), other environmental factors or genetics.

Chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. (R)

Leptin is more of the inflammatory marker, as it responds to inflammatory cytokines from fat tissue. (R)


Leptin suppresses food intake and increases energy expenditure at least partially by activating POMC and CART neurons and by suppressing NPY and AgRP. Other metabolic signals apart from leptin regulate the POMC-expressing neurons in the ARC; these include glucose, insulin, the gut peptide PYY3–36 and serotonin (R).

The fact that leptin elevates BDNF in the hypothalamus suggests that BDNF might mediate the effects of leptin on food intake and energy homeostasis (R).

In the ventral tegmentum (an area important for cognition, motivation, orgasm, drug addiction and intense emotions relating to love), leptin reduces dopamine neurotransmission and makes food less rewarding (R).

More about Leptin:


Leptin causes inflammatory fatigue (RR2).

Leptin inhibits orexin (R, R2), which can cause fatigue.

Leptin increases were associated with greater fatigue scores in people with CFS, and it’s assumed that leptin plays a causal role in CFS (R).

Leptin levels in the blood are also associated with fatigue severity in patients with chronic hepatitis C and irritable bowel syndrome [RR2].

Endotoxin in both rodents and humans leads to increased leptin levels [R,R2].

Leptin increases the release of the proinflammatory cytokines TNF-alpha, IL-2, IL-6, and IL-12 [RR2].

Multiple studies have demonstrated elevated levels of circulating leptin in chronic inflammatory conditions [RR2].

Leptin displays a circadian rhythm, where it peaks at midnight and is at the lowest point between 9AM-12PM.  The timing of your meals affects when you have a peak of leptin (R).

In people with CFS, leptin increases more in response to cortisol (R).

Leptin provokes the release of proinflammatory cytokines from many cell types, including microglia in the brain (R), and is a mediator of cytokine-induced sickness behavior (R).

Like BDNF, leptin facilitates synaptic plasticity in the hippocampus (R).

Leptin facilitates long-term potentiation (LTP) and long-term depression and spatial learning (R).

Leptin increases hippocampal plasticity (R).

Leptin also affects the growth of blood vessels and bone; the immune system; glucose- and fat metabolism and the reproductive system. (R)

Leptin promotes the growth and spread of cancer and is  pro-inflammatory. In terms of both structure and function, leptin resembles IL-6. (R)  Hence, this is one reason why obesity is a risk factor for cancer.

Elevated leptin concentrations are associated with elevated white blood cell (WBC) counts in both men and women. (R)  This may be one reason why the thin people that I deal with seem to have WBC counts in the lower range, as they are usually thin.

Leptin increases the stress response (or the HPA axis) and lowers heart rate variability. (R)

Leptin increases TRH (via STAT3 and MSH/MC4R) (R) and MSH (R).

Leptin inhibits AMPK an energy sensor which is activated by decreased ATP.

Leptin activates mTOR in the hypothalamus, which reduces appetite [R].

Leptin is increased by:

Leptin is increased after meals – more by carbohydrates then by fat in both obese and healthy people (R, R2).

When stressed, you release leptin and the more you release, the more you eat comfort foods after. (R)

It is speculated that leptin responds specifically to inflammation from fat cells. (R)

Testosterone, sleep, emotional stress, caloric restriction, and body fat levels are factors that acutely affect leptin levels. (R)

Lectins are proteins that bind to sugar molecules.  Leptin receptors have these sugar molecules that lectins like to bind to such as ConA (in legumes) and WGA (in wheat).  If the sugar molecules on leptin receptors are bound (or removed), then the receptors don’t function nearly as well (R).

  • Short-term fasting (24–72 hours). (R)
  • Leptin can be reduced or increased by sleep deprivation (contradictory) (R)
  • Testosterone. (R)
  • Exercise (contradictory).(R)
  • Estrogen. (R)
  • Emotional stress. (R)
  • Dexamethasone. (R)
  • Insulin. (R) – Leptin increases 4–6 hours after meals in response to insulin secretion (R).
  • Obesity (R)
  • Restful sleep – in non-obese individuals (i.e., 8–12 hours of unbroken sleep) – can increase leptin to normal levels.  (R)
  • Sleep apnea – in obese people, but it decreased after CPAP treatment.  (R)
  • Glucosamine (and hexosamines) (in pancreatic beta-cells) (R)

Leptin is decreased by:

Alcohol compared to other calories (R).

You can measure Leptin levels.

2) Insulin


Insulin has mixed effects – it reduces appetite, but can increase fat mass.

Insulin is one of the big 4 hormones that determine weight.

Insulin is a hormone that causes satiety.(R)

The problem comes when you’re insulin resistant.   Your body/brain won’t get the message that insulin is trying hard to convey.  In this way, insulin resistance promotes hunger. You eat, and insulin is released, but your body tells you to eat some more despite the ability of insulin to act as a satiety hormone.

Insulin puts glucose in your liver, muscle and fat cells. (R)

Insulin forces fat cells to take up blood fat (lipids) and also converts those fat to other kinds of fat (triglycerides). (R)

Insulin decreases the release of fat in your fat cells, so you store fatter. (R)

Insulin decreases the breakdown of protein from your muscle and also increases uptake of protein/amino acids – hence why body building like to spike insulin with glucose. (R)

Lowered levels of insulin cause liver to convert glycogen to glucose and excrete it into the blood. (R) This is one reason why many of my thin clients with low insulin also often have higher blood glucose.

Insulin also decreases the production of glucose from protein. (R)

So we see insulin can be protective in many ways by lowering blood glucose…. It does this by converting glucose to glycogen, increasing glucose uptake (in muscle, liver and fat) and decreasing glucose production from protein.

It’s also protective by storing fat (higher blood fat is not good).

Insulin is also bad in that it decreases autophagy or breaking down of damaged cellular parts (organelles).(R)  When you decrease autophagy, your cells don’t work as well.

Insulin lowers blood potassium.  It does this by forcing cells to absorb blood potassium.  (R)

Insulin forces artery wall muscles to relax, thereby increasing blood flow, especially in micro arteries. A lack of insulin reduces flow.  (R)  In the thin people I deal with, they often feel cold.  One of the many reasons is because of low insulin, which reduces blood flow.

Insulin increases the secretion of hydrochloric acid by parietal cells in the stomach. (R)  In my thin clients, they are more likely to have lower HCL levels.  One reason is because of lower insulin.

Insulin decreases kidney salt excretion. (R)  This is one reason why my clients with low insulin have lower blood pressure, as salt retention increases blood pressure.

You can check your insulin levels.

3) Neuropeptide Y (NPY)


NPY causes weight gain,

Neuropeptide Y (NPY) is one of the big 4 hormones that determine weight.

NPY injection causes rats to binge.

NPY causes the creation of new fat cells and fat to build up in the belly. (R)

Leptin suppresses food intake and increases energy expenditure at least partially by suppressing NPY (R).

Studies of mice and monkeys show that repeated stress and a high-sugar diet stimulate the release of NPY. (R)

NPY is increased when you restrict calories, and this is part of the mechanism by which calorie restriction increases longevity. (R)

Activation of CREB in the paraventricular nuclei and ventromedial hypothalamus is the mechanism by which this happens. (R)

NPY is actually an anxiety-reducing hormone.

NPY is increased by the stress response -specifically cortisol (R) and CRH– in order to ameliorate it.

NPY then goes on to lower all hormones in the stress pathway, including CRH, ACTH, and Cortisol.  It also induces sleep. (R)

NPY is released also by cold or heat stress. (R, R2)  This is the main mechanism by which you feel relaxed and/or sleepy after a cold shower or sauna.  Vagus nerve stimulation and TRH is probably the other mechanism with regard to cold.

Adaptogens increase NPY release and this is thought to be one mechanism by which they cause stress resilience. (R)

Special forces soldiers actually have increased NPY compared to regular soldiers, and this probably contributes to their specialness. (R)

Higher levels of NPY also protect against PTSD. (R)

On the downside, NPY increases cancer risk, probably by increasing angiogenesis. (R)  I always noticed the most resilient people who didn’t notice much from lifestyle modification – those who didn’t have autoimmune problems- were the ones most likely to succumb to cancer.  If autoimmunity doesn’t get you, cancer will- if you’re not taking care of your health.

So NPY can decrease the damage done by stress, but you’ll become fat in the long term.

This accords with my experience that thin/anxious phenotype, who often have a harder time dealing with anxiety than the overweight folks.

Amphetamines induce appetite suppression (and anxiety) by inhibiting NPY. (R)

Overall, NPY is a good thing, and being a higher NPY releaser is a plus in the modern environment, but it has its costs.   The answer is to get your NPY from intermittent stressors, not from abusing food or from chronic stress.

4) Cortisol


Cortisol causes weight gain, on the whole.

Cortisol is one of the big 4 hormones that determine weight.

Cortisol secretion is also elevated in obesity, but blood levels are normal because it gets deactivated.  In fat tissue itself, cortisol is elevated. (R)

Animal and human studies have demonstrated that cortisol injections are associated with increased appetite, cravings for sugar, and weight gain. (R)  I can verify this with my experiments with Hydrocortisone.

It has been thought that cortisol directly influences food consumption by binding to receptors in the hypothalamus. This can stimulate an individual to eat food that is high in fat and/or sugar. (R)

Women who secreted more cortisol during and after stressors chose to consume more foods high in sugar and fat. (R)

Cortisol also indirectly influences appetite by regulating other hormones that are released during stress such as CRH, leptin, and NPY.

Cortisol increases leptin secretion from fat cells. (R)

Cortisol decreases insulin secretion and increases insulin resistance, which will raise insulin levels in the longer term. (R)

Its anti-insulin effects are there to increase glucose uptake and usage in the brain, heart, and muscles.  (R)  These are the places that need it most when you’re running from a lion.

Cortisol increases glucose production and reduces glucose uptake in certain places. (R)

The good part of cortisol is to decrease hypoglycemia, by increasing blood glucose.  When I have a thin client who suffers from hypoglycemia, I know their cortisol levels are chronically or intermittently low.  This is the main defining feature that separates the hypoglycemics from those who don’t get hypoglycemic often.

However, Cortisol reduces glucose delivery to some tissues by impairing local blood flow (it increases blood flow to the heart). (R)

Cortisol also has an acute fat busting effect in animals, but chronically high cortisol doesn’t seem to have this effect.  Cortisol also breaks down muscle. (R)

Chronic cortisol excess in rodents paradoxically induces weight loss rather than weight gain. (R)

In Cushing’s syndrome, where cortisol is very high, there is an accumulation of fat in the belly, neck, and cheek, but a decrease of fat in many other places. (R)

There may also be an accumulation of fat in the liver in Cushing’s syndrome (R).

Cortisol simultaneously stimulates both glucose storage (glycogen synthesis) and glucose breakdown (glycogenolysis). (R)  It depends on other factors like insulin levels.

When they’re low insulin and high adrenaline, cortisol may cause a more effective release of fuel and higher glucose output. When there’s high insulin, cortisol may promote glycogen accumulation. (R)

Some other important effects:

  • Cortisol decreases the Th1 response and favors more of a Th2 response.  It inhibits IgM and IgA, but not IgE antibodies. (R)
  • Cortisol stimulates many copper enzymes, probably to increase copper availability for immune purposes. (R)
  • Cortisol stimulates internal antioxidants such as SOD. (R)
  • Cortisol reduces bone and collagen formation. (R)
  • Cortisol causes the pumping of potassium out of the cell, which is the opposite effect of insulin. (R)
  • Cortisol increases urination (R). I ask in my questionnaire whether people urinate frequently to get a pulse on their cortisol levels.  Because some people have reduced cortisol after a while of chronic stress.
  • Cortisol will cause higher blood pressure by retaining sodium, excreting potassium and by making your blood vessels contract. (R, R2)  This is why I ask people what their blood pressure number is exactly.  The people with high blood pressure are usually the people with high cortisol.
  • If you’ve got high cortisol, you will do worse with a high salt diet and you will be potassium deficient in the long term (few people as it gets the RDA).  But taking potassium supplements is not simple because the deficiency is in your cells, not your blood. Also, potassium raises cortisol, which isn’t good if you already have high levels. Cortisol is anti-inflammatory, but it can also cause arthritis by inhibiting collagen formation and also by lowering cell potassium.  Cell potassium is always low in in rheumatoid arthritis.(R) The answer is to reduce stress.
  • Cortisol also reduces calcium absorption (R), so you will be deficient in calcium (few people as it gets the RDA).
  • Cortisol stimulates stomach acid secretion. (R)
  • Cortisol delays wound healing. (R)

See a comprehensive list of reasons why your cortisol is low or high.

Also, see why stress is bad.

You can check your cortisol in different ways, all of which are useful…

  • Cortisol (AM) and Cortisol (PM).
  • Cortisol (24-hour urine) – urine is a reliable indicator (as is hair) (R)
  • Cortisol Rhythm (4 salivary samples) – also useful…(R)  People with primary insomnia have an awakening cortisol of 3.6 ng/ml (9nmol/l).  Healthy controls have 4.8 ng/ml (12 nmol/l).  (R)


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