The negative effects serotonin has on your physique: the “anti-depressant” molecule with depressing properties

For the past decades white lies and muddied research established serotonin as a beneficial neurotransmitter for mental and physical health. However, more and more research, that reveals the truth about serotonin, is starting to surface and topple that muddy tower of serotonin “goodness” down.

Serotonin is turning out to be much more of a downer than an upper, and not just from a mental perspective, but physical as well.

Serotonin is elevated during stress to help the body cope with the event, but when serotonin stays chronically elevated, it brings many unwanted side effects.

For the sake of this article, we’re only going to focus on how serotonin affects your aesthetics and not so much on the other health or mental aspects thereof.

Serotonin is produced from the amino acid tryptophan by the two enzymes, tryptophan hydroxylase 1 (TPH1) and 2 (TPH2).

TPH1 produces 95% of the total body’s serotonin in the gut.

TPH2 produces serotonin in the nervous system and acts mostly in the brain.

Serotonin that’s produced in the gut through TPH1 cannot cross the blood brain barrier so it does not have an effect on the brain.

So what does serotonin do in the body?

Two “good” actions of gut derived serotonin is that it promotes peristalsis and can help with a bowel movement; it also promotes nutrient absorption.
However, the pathogenesis of colitis, that is, inflammation of the inner lining of the colon, has been attributed to serotonin. Serotonin has also been implicated in various gastrointestinal diseases, such as inflammatory bowel disease, irritable bowel syndrome, and celiac disease.

But when the gut starts promoting too much serotonin, it leads to obesity, organ damage, fibrosis, etc.

Serotonin promotes weight gain by:

  • Increasing nutrient absorption. Absorbed food has to go somewhere so it’s either used as energy or stored as fat. In this case, it’s most likely stored because serotonin promotes the storage of nutrients.
  • Promoting lipogenesis.
  • Promoting fat accumulation in the liver, leading to fatty liver, liver fibrosis and liver failure.
  • Promoting insulin secretion. This effect is good, but too much insulin secretion produces insulin resistance and excess fat storage.
  • Reducing lipolysis, which is the process of mobilizing stored fat.
  • Reducing the metabolic activity of brown and beige adipose tissue seen by reduced Ucp1 mRNA in fat cells treated with serotonin. Serotonin also prevents the browning of fat cells. Brown fat is highly metabolically active and produces heat and fat loss. Serotonin also reduces brown adipose tissue cell sensitivity to
    β-adrenergic activation (R). Taking a 5-HT3 antagonists, such as ginger or Ondansetron synergistically promotes lipolysis with a β3-adrenergic receptor agonist such as caffeine or bitter orange extract.
  • Inhibiting futile cycling. A few cycles include ATP cycling, creatine cycling, lipogenesis and beta-oxidation cycling. These are processes where the body creates something and breaks it down again in a “futile” cycle. Futile cycles promote health and energy expenditure.
  • Inhibiting the enzyme DIO2 (which converts thyroid hormone T4 to T3) and PGC-1α (which increases mitochondrial number and size).
  • Disrupting steroidogenesis (R, R, R). Low androgens lead to a loss in muscle mass and a gain in fat mass.
  • Inhibiting thyroid hormone production, which will also have a negative effect on body composition and steroidogenesis (R, R).

Inhibiting serotonin synthesis with the use of drugs is currently being used against obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) (R). True story.
Mice that lack central serotonin synthesis, due to reductions in TPH2, are leaner and have increased energy expenditure.

The use of selective serotonin reuptake inhibitors (SSRIs), which inhibit SERT function and prolong serotonin neurotransmission, have been linked to modest increases in weight gain and the incidence of type 2 diabetes.

Let’s dive a little deeper into this whole serotonin business.

Serotonin binds to 7 receptors, of which there are 14 subtypes.

Specifically, 5-HT2A, 2B, 2C and 3 are involved in fat gain.

  • 5-HT2A promotes the release of cortisol (which is associated with metabolic disorders and central obesity) and prolactin, inhibits lipolysis and increases adipogenesis (the creation of new fat cells) (R, R). Inhibition of liver 5-HT2A may be an effective target for reducing non-alcohol fatty liver disease (NAFLD).
  • 5-HT2B promotes lipolysis and gluconeogenesis and inhibits liver glucose uptake under fasting conditions (R). Through this receptor, serotonin is also able to reduce liver regeneration and cause fatty liver, liver fibrosis and eventually liver failure by producing TGF-β1.
  • 5-HT2C increases cortisol release. Through this receptor serotonin suppresses appetite. A lot of appetite suppressant drugs act on this receptor.
    But do you know how it lowers appetite? Through dopaminergic neurotransmissions. So instead of promoting serotonin to lower appetite, boost dopamine instead. That is the way it works after all.
  • 5-HT3. Interestingly, similar to TPH1 inhibition, 5-HT3 inhibition also results in a lean phenotype (R). 5-HT3 is highly expressed in the central nervous system, which means that serotonin produced through TPH2 can also promote obesity, not just TPH1. Furthermore, antagonizing 5-HT3 prevents fatty liver (R).

In summary

Serotonin increases lipid accumulation in the liver, promotes lipogenesis and adipogenesis, increases glucose uptake, reduces browning, increases insulin secretion, reduces thermogenesis.

In short, serotonin promotes the storage of nutrients and is a stress/hibernation neurotransmitter.

Four main ways to lower serotonin is to keep glycogen stores full, prevent stress and a rise in cortisol and to lower estrogen and inflammation.

1) When glycogen stores start to dip, the body senses it as a stressor and increases serotonin, which, through the 5-HT2 receptors, increase cortisol, gluconeogenesis, lipolysis and inhibit liver glucose uptake. Remember, with high serotonin, these effects will persist even when glucose is consumed.

2) Stress, either physical (prolonged exhaustive exercise) or mental, will increase serotonin. These adaptogens:

…can help to keep stress/serotonin at bay. My personal top two favorites are tribulus and rhodiola.

3) Estrogen is one of the most potent inducers of serotonin. Estrogen increases TPH, enhances serotonin receptor density and sensitivity, lowers MAO-A (which breaks down serotonin, thus leading to less serotonin breakdown) and SERT (which clears serotonin from extrasynaptic space to reduce it’s action).

5 most potent natural aromatase inhibitors include:

4) And last but not least, inflammation is another potent inducer of TPH and will increase serotonin. Anything that lowers inflammation, such as vitamin E, aspirin, tetracycline, etc., lowers excess serotonin levels.

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