Vitamin A and Weight Gain

It is estimated that in 2016 about 70% of the U.S. population was overweight (Hales, Fryar et. al 20218), and about 40% of the population was considered obese. Contrary to what is sometimes claimed, being overweight or obese is not a lifestyle choice, and often people begin gaining weight despite their greatest efforts not to. Obesity is a medical condition that requires treatment before it progresses to diabetes, fatty liver disease (NAFLD) and heart disease. Unfortunately, the effectiveness of today’s drugs is limited, and similarly lifestyle changes (such as exercise and diet modifications) are often strenuous and difficult to comply with. The fact that Vitamin A may play a significant role in weight gain is virtually never discussed.

What is the purpose of body fat?

Nothing the body does is accidental, and every effect is preceded by a cause. A little known fact about adipose tissue (body fat) is that it’s also the storage site of various toxins, and acts as a kind of graveyard for foreign substances that the body has difficulty eliminating.

In general, any substance can be water-soluble or fat-soluble. Substances that are water-soluble, for example sugars, many proteins and most vitamins dissolve easily when they are mixed with water. Fat-soluble substances like oils, pharmaceutical drugs and vitamins A, D and E do not easily dissolve in water, which is a requirement for them to leave the body. Fat-soluble substances are able to re-circulate by dissolving through the walls of the small intestine into the portal vein, and from there they re-enter the liver and blood. Water-soluble substances cannot re-circulate like this and are eliminated through urine, however they also can’t cross the blood-brain-barrier and therefore do not produce psychotropic effects, which is why most drugs are fat-soluble.

The body has various tools to prevent this re-circulation of substances. In Phase I reactions, the body inserts one or more oxygen atoms into the molecule, which is sometimes already enough for it to be eliminated. The stimulant drug amphetamine, for example, is transformed by a liver enzyme called cytochrome P450 2D6 (CYP2D6), which introduces a hydroxy group (one oxygen and one hydrogen atom; OH) at the fourth carbon atom of an amphetamine molecule (de la Torre, Yubero-Lahoz et. al 2012). The resulting substance, 4-hydroxyamphetamine, can no longer re-circulate and is eliminated in urine.

Some substances are still not water-soluble enough to be eliminated after Phase I reactions. The anxiety medication diazepam, for example, gets converted to 3-hydroxydiazepam (temazepam; Mandelli, Tognoni et. al 1978), which is still very fat-soluble and has psychoactive effects similar to those of diazepam. In fact, temazepam is also sold as an anxiety drug under the name Restoril. In this case, the body performs a more complex  Phase II reaction and binds the substance to glucuronic acid (which is derived from glucose). This is normally sufficient to make substances water-soluble enough to be eliminated in feces.

Substances can become dangerous when the body is either unable to perform these Phase I and Phase II reactions, or a substance is still too fat-soluble after the reactions. It then becomes trapped in the body with nowhere to go. This is especially problematic if the substance has biological effects. The body now has two remaining options: it can either straight up attack the substance with the immune system, as if it was a bacteria or virus, which is effective but causes damage to cells and inflammation. The other option is to store the substance in adipocytes (fat cells), where it is relatively isolated and cannot cause any harm.

This mechanism of dumping toxins into fat cells is the reason why some substances—especially in California—can cause cancer much later on in life. PCBs, for example, are a group of environmental pollutants that were widely used before being banned in 1978. They cause damage to different organs in the body but are mostly known for being highly carcinogenic (causing cancer). It has been estimated that their half lives (time until 50% is eliminated) can range from 1 year (PCB-81) to 20 years (PCB-189; Milbrath, Wenger et. al 2009). That means that someone who was exposed to 10 mg of PCB-189 when they were 20 years old will still have about 2.5 mg in their fat cells when they are 60 years old!

What happens to Vitamin A in the body?

Vitamin A (retinol) is a type of alcohol that, similar to alcoholic beverages, must undergo multiple transformations before it can participate in Phase I and Phase II reactions. Let’s first see what happens to regular alcohol (ethanol; Holford 1987):

• Ethanol is converted to ethanal (acetaldehyde), which is responsible for the hangover and toxic effects produced by alcohol consumption
• Ethanal is converted to ethanoic acid (acetic acid), which  is the main ingredient of vinegar
• Ethanoic acid happens to be the substance from which the body synthesizes fat (even without alcohol consumption), which is why it does not undergo Phase I/II reactions and is instead turned into fat

Now, let’s look at the theoretical transformation that retinol must undergo before it can be eliminated (Kohlmeier 2015):

• Retinol is converted to retinal, which is highly toxic but plays a role in vision because of its ability to absorb light (Kim, Sparrow 2021)
• Retinal is converted to retinoic acid, which is highly toxic and can cause cells to either self-destruct or reproduce at unusually high rates (De Genaro, Simón et. al 2013)
• Retinoic acid undergoes a Phase I reaction to the mysterious 4-hydroxyretinoic acid (4-OH-RA) (Shimshoni, Roberts et. al 2012)
• 4-OH-RA undergoes a Phase II reaction to 4-OH-RA glucuronide, which is finally water-soluble enough to be eliminated (Samokyszyn, Gall et. al 2000)

This is the process through which retinol should theoretically be eliminated. However, in practice, problems occur at every possible step:

• Retinol is not converted to retinal (except in the eye), likely because of its toxicity; in fact the body has developed an extremely elaborate system to instead convert retinol into retinyl palmitate, which is deposited into fat cells
• If small amounts of retinal happen to be produced anyways they are immediately converted back to retinol (Giménez-Dejoz, Kolár̂ et. al 2015), likely because retinoic acid is even more toxic
• When retinoic acid comes close to cell membranes it can undergo a spontaneous transformation, which damages the structure of the cell and produces 5,6-epoxyretinoic acid (Shih, Lin et. al 1997), a free radical that initiates a severe chain reaction causing major damage unless it is stopped by antioxidants (Samokyszyn, Freyaldenhoven et. al 1997)
• If 4-OH-RA does not rapidly undergo a Phase II reaction to 4-OH-RA glucuronide, it will instead be converted to either 4-oxo-RA, which is at least as toxic as retinoic acid itself (Pijnappel, Hendriks et. al 1993) and can no longer undergo Phase II reactions, or to other substances derived from 4,16-(OH)₂-RA which have not yet been identified by scientists (Topletz, Thatcher et. al 2012)

Let’s take a closer look at the system the body has developed to store retinol. Firstly, because retinol dissolves through cell membranes so easily it must be attached to a transport protein (retinol binding protein 4; RBP4) before it is released into the bloodstream. This is similar to dining at a restaurant: when you arrive, you could theoretically take a seat at any available table, you could even forcibly remove other patrons and take their tables. The restaurant obviously wants to avoid that, which is why they employ hosts and waiters to transport you to your designated table.

This distribution of substances with transport proteins is not unique to retinol, in fact many other substances are transported in the same fashion (Yee, Aldeghi et. al 2019). Normally, after some time, the substance spontaneously dissociates from the transport protein and enters cells through diffusion. This ensures that substances are distributed equally throughout the body. To continue the restaurant analogy, when you arrive at the restaurant, the waiter walks around the restaurant with you on a random path, and after some time tells you “please, sit at the table closest to you”.

The retinol transporter RBP4, however, works differently. It does not spontaneously dissociate from the retinol, and instead delivers it to certain types of cells that have a unique receptor in their membrane called stimulated by retinoic acid 6 (STRA6). When retinol and RBP4 interact with STRA6, multiple things happen:

• Retinol is released from RBP4 and transferred to STRA6, which lifts it through the cell membrane and delivers it to another transport protein called cellular retinol binding protein 1 (CRBP1; Berry, O’Byrne et. al 2019)
• STRA6 initiates a chain reaction by activating a protein called Janus kinase 2 (JAK2), which ultimately causes the cell to stop burning fatty acids and begin synthesizing new fatty acids
• CRBP1 transports the retinol to another enzyme found deep within the cell called lecithin retinol acyltransferase (LRAT; Marwarha, Berry et. al 2014)
• LRAT combines retinol with a fatty acid, often palmitic acid, producing retinyl palmitate, which stays in the cell indefinitely

Let me repeat the most important part: Retinol causes certain cells, including fat cells, to stop burning fat and begin synthesizing even more fat!

Imagine you arrive at the restaurant with a gun and begin threatening other patrons. What would happen? Most likely the waiter would call 911, and escort you to the policeman responding to the incident. The policeman would then transport you to jail, where you would be deposited indefinitely. If the policeman is especially meticulous (like STRA6 is), he would also alert the precinct that he is on his way with you in the back of his patrol car, and ask them to construct another jail cell to replace the vacant cell you will soon occupy.

How does retinol prevent fat burning?

It seems hard to believe that a single substance can cause such profound changes to fatty acid metabolism, which is why it's crucial to understand the mechanism through which retinol produces these changes.

In general, the body constantly manufactures new proteins from DNA. DNA can be thought of as a library containing tens of thousands of books, and each book contains instructions to build a specific protein. The library also contains printers (RNA polymerase enzymes) which make copies of books (transcription of genes), and these copies are later assembled into proteins outside of the library. Therefore, in order to manufacture new proteins, books must first be removed from their shelves and taken to the printer.

Substances that are capable of doing this are called transcription factors, and one transcription factor usually doesn’t just bring one book to the printer, but rather a whole stack of books that are part of a certain group, for example only true crime books, or only romance novels, or only magazines that start with the letter A and were written between January and February of 2004. These DNA sections  containing a group of books are called response elements. Since manufacturing proteins can be very dangerous, there are many failsafes in place to prevent abuse of the printers. Co-repressors are substances that prevent transcription factors from bringing books to the printer. Additionally, multiple transcription factors often need to work together to bring books to the printer.

To give an example, consider the aryl hydrocarbon receptor (AHR; Probst, Reisz-Porszasz et. al 1993). AHR receptors are transcription factors that can be activated by certain foreign substances, such as the PCBs described earlier. When AHR is activated by a substance like PCB-189 in the liver, it recruits another transcription factor called AHR nuclear translocator (ARNT). ARNT chaperones AHR into the cell’s nucleus (where DNA is located), and together they begin bringing certain books to the printer. The books they carry to the printer are part of a group called xenobiotic response element (XRE), and books from this group contain instructions for proteins that help eliminate PCB-189. Additionally, some books contain instructions to build proteins that destroy AHR, and one book even contains instructions for a protein called AHR repressor (AHRR), which is a co-repressor for AHR (Evans, Karchner et. al 2008). Once these proteins are assembled, AHR is destroyed by them, the printer thus stops making copies, and the sequence of events is complete.

Retinol does the same thing when it comes into contact with STRA6 receptors. Unlike AHR, STRA6 remains in the cell membrane and activates a signaling pathway called the JAK-STAT pathway (Berry, Levi et. al 2014). It is believed that STRA6 receptors have a protein called JAK2 attached to them that can either be turned on or off, and that is normally off. When retinol interacts with STRA6, STRA6 turns JAK2 on through a chemical reaction called phosphorylation. Once JAK2 is turned on, it can turn on signal transducer and activator of transcription 5 (STAT5) transcription factor proteins that normally float around within the cell in an inactive state. This activation of STAT5 causes it to look for a second STAT5 transcription factor, and once found, they migrate to the cell’s nucleus together. In the nucleus, they begin copying books from the STAT5 response element (Dentelli, Trombetta et. al 2009).

The STAT5 response element contains instructions for many different proteins, which makes research more difficult, since not all of the proteins are obviously related, and we don’t even know what many of them actually do. Further complicating matters is the fact that the STAT5 response element was confirmed to contain a book with instructions for a different transcription factor called peroxisome proliferator activated receptor gamma (PPARG; Kawai, Namba et. al 2007). PPARG on its own can start copying books from a whole different group called the PPAR response element, without any help from STAT5. Additionally, the STAT5 response element contains instructions for a protein called suppressor of cytokine signaling 3 (SOCS3; Huang, Zhao et. al 2013). Once SOCS3 is assembled it turns off both STAT5 and JAK2, completing the sequence of events.

Some models have predicted more than 2,500 genes controlled by PPAR transcription factors, of which 225 have been confirmed in experiments so far (Fang, Zhang et. al 2016). It is generally accepted that PPAR alpha (PPARA) and PPAR beta (PPARD) mainly control transcription of fat-burning genes, whereas PPARG mainly controls transcription of fat-making genes (Ebert, Kisiela et. al 2016).

One thing we know for sure is that PPARG is absolutely required for the body to create new fat cells. Scientists were able to genetically modify mice so that their DNA no longer contained the PPARG gene, and therefore their cells could no longer manufacture the PPARG protein encoded by that gene. These gene knockout mice were completely unable to build any adipose tissue (Ahmadian, Suh et. al 2013), no matter how much fatty food they were given!

Not eating Vitamin A causes weight loss

It has been repeatedly demonstrated in studies with animals that removing Vitamin A from the diet leads to significant weight loss:

• Growing mice that had Vitamin A removed from their food gained 15% less weight than normal mice (Tian, Nichols et. al 2018)
• Growing rats that had Vitamin A removed from their food gained 30% less weight in 8 weeks (Kuang, Wei et. al 2019)
• A different study confirmed that this was directly caused by Vitamin A, as even after the scientists made sure that both groups of mice consumed the same amount of calories, those that did not eat Vitamin A gained less weight (reviewed by Chen 2021)
• Growing calves (the children of cows) were found to gain weight and body fat after just a single dose of Vitamin A! The scientists also confirmed that the amount of weight gained was proportional to the amount of Vitamin A given (Harris, Wang et. al 2018)
• Another study measured the amount of fat that mice burned, and found that after mice stopped eating Vitamin A their mitochondria burned an incredible 30% more fat! (Oliveros, Domeniconi et. al 2007)
• Fully grown mice that were given a high-fructose diet designed to make them fat lost 25% of their body weight after Vitamin A was removed from the diet, and they lost 40% of their adipose tissue! (Raja Gopal Reddy, Pavan Kumar et. al 2016)

So it really seems like we’re onto something here, right? You would think that these findings would have motivated researchers to find out what happens when humans stop eating Vitamin A, right? Well, you’ll probably be very surprised to learn that—to the best of my knowledge—the last time anyone tried something like this was in the year 1940! (Wagner 1940) In that study, carried out in Nazi Germany, participants were assigned high-fat diets containing 3,000–5,000 calories per day that did not contain Vitamin A. After 6 months participants had lost an average of 10 pounds, and only one of the ten participants did not lose weight. To confirm that the Vitamin A was indeed at fault, participants were then given Vitamin A supplements while sticking with the same diet. Over the next 4.5 months, all ten subjects gained an average of 12 pounds!

What are the arguments exonerating Vitamin A?

A limited number of studies have been carried out where humans were given large doses of Vitamin A daily, usually for a short period of time, and their weight, body fat and liver values were monitored. In one randomized, double-blinded and placebo-controlled study, participants did not significantly gain or lose weight after taking 800% RDA for four months, and body fat composition did not change significantly either (Farhangi, Keshavarz et. al 2013). The only effects were modest increases in triglycerides, cholesterol and liver enzymes (AST and ALT increased by 25–50% and 3–23%, respectively).

One explanation could be that the liver must be saturated with Vitamin A before weight gain occurs. When the liver’s capacity of storing Vitamin A is reached, it is conceivable that any excess retinol will be released into the bloodstream and taken up by other cells, which then start manufacturing fat (to bind the retinol) and fat cells (to store the retinol). Blood tests have shown that the amount of retinol transport protein (RBP4) in blood is significantly correlated with body weight and insulin resistance (Wang, Huang et. al 2020). Even though RBP4 transports retinol, and the obvious idea would therefore be to reduce retinol intake, scientists have started developing drugs to reduce RBP4 levels instead.

Conclusion

We know for certain that retinol directly causes the body to start synthesizing proteins involved in the production of fatty acids. While we can’t say for sure how much Vitamin A actually contributes to obesity overall, animals have consistently lost roughly a quarter of their body weight after Vitamin A was removed from their food, even after controlling for calories, and we can be fairly certain that similar effects should also be observable in humans.

Therefore, we desperately need high quality, peer reviewed studies to determine whether removing Vitamin A from the diet produces weight loss in humans too. These studies should be easy enough to carry out.

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