The AhR is the Keymaster to Torpor

My last posts were viewed by some as pessimistic in a “once you’re obese, you are stuck” kind of way.  I don’t believe that and very soon I will start writing about solutions.  Having said that, this post will perhaps seem pessimistic if you thought the previous ones were.  I’m working through the basic mechanisms that control the switch into obesity and a torpid metabolism.  Once we have understanding, then we can think about solutions.

This post will complete the chain of events that begins with consuming polyunsaturated fats (PUFA) and ends in obesity and torpor.  It also connects the dots between obesity and organic pollutants.

I have said that PPAR gamma is the Gatekeeper that controls entry into torpor and that oxidized PUFA is the key that unlocks it.  What I haven’t talked about is how the PUFA gets oxidized.  The thing about PUFA is that it can and does oxidize on its own but in the human body it is MUCH more likely to be oxidized by an enzyme.  

The enzymes COX1 and COX2 convert arachidonic acid – derived from linoleic acid -into prostanoids.  Prostanoids are oxidized PUFA which play a role in inflammation.  COX1 and COX2 are blocked by aspirin and ibuprofen.  If you eliminate the oxidized PUFA, your headache goes away.

The Aryl Hydrocarbon Receptor (AhR)

This unfortunately named “nuclear receptor” isn’t even really a receptor in the classical sense.  It’s not on the cell surface, it lives in the cytosol (inside the cell) and when it binds it’s “ligand” – the thing it recognizes and which turns it on – it goes into the nucleus and turns on other genes.  

One of its functions is to help break down environmental toxins.  It does this by turning on several genes which code for oxidizing enzymes such as the cytochrome P450s, including the genes CYP1A1, CYP1A2 and CYP1B1.^​1​  Cytochrome P450s oxidize things.  We break down toxins by oxidizing them.

For instance, the AhR is turned on by the polycyclic aryl hydrocarbons found in roasted coffee and CYP1A2 is responsible for caffeine metabolism.  Polymorphisms in the CYP1A2 region are associated with increased coffee consumption.  I am a coffee addict, as is my whole family, which means we likely have an active form of CYP1A2.^​2​

CYP1B1 Turns Arachidonic acid into known PPAR gamma activators

This study^​3​ showed that in the laboratory, CYP1B1 in the presence of NADPH turns arachidonic acid – a downstream product of linoleic acid – into known PPAR gamma ligands (activators) 15-HETE^​4​ and 12-HETE^​5​, among others.  CYP1B1 and the linoleic acid product arachidonic acid create the key to turn on PPAR gamma and thus the torpid metabolism.

This is a lab experiment, however, is it relevant in the real world?  Does it have the same effect in the liver of a living organism – the place where torpor is triggered?

Persistent Organic Pollutants

PCBs and dioxins are Persistent Organic Pollutants (POPs) – compounds with a very long halflife that persist in the environment for 100s of years.   They are produced from industrial processes such as coal burning and paper manufacturing, and from tailpipe emissions and trash incineration.  PCBs are famously high in the Hudson River. Dioxins have the unfortunate ability to bio-accumulate in fat tissues of animals (and humans) who consume them.  

Dioxins are known activators of the AhR.  If you feed dioxins to a mouse, you can see whether turning on the AhR creates these oxidized PUFA in real life.

The AhR oxidizes PUFA

This study^​6​ looked at the effects of dioxin treated mice with or without AhR.  I’m going to focus on results in the liver since that is where lipogenic genes tend to be upregulated in obesity.   They found that:

1. Dioxin did not increase eicosanoid (oxidized PUFA) levels in mice without AhR. Thus, the observed increases in the eicosanoids induced by dioxin are dependent on AhR.
2. In the absence of dioxin, the wild type and Ahr lacking mice exhibited similar levels of eicosanoids.
3. In the liver, dioxin increased the levels of several epoxides of arachidonic acid (EETs), a-linolenic acid (EpoDEs), EPA (EpETEs) and DHA (EpDPEs), in several cases more than 10-fold. Dioxin increased the levels in the liver of an even greater number of the diols of arachidonic acid, EPA and DHA (DHETs, DiHETEs and DiHDPEs, respectively) and also increased the levels of the diols of linoleic acid (DiHOMES). 

So yes, The AhR creates oxidized PUFA in response to dioxin.

Blocking the AhR Lowers CYP1B1 and prevents Diet Induced Obesity in mice

When mice are fed a Western diet, they make lots of CYP1B1 and become obese.  When a pharmaceutical is used that blocks the AhR, CYP1B1 expression is dramatically reduced and obesity is prevented.  This is despite the fact that whether or not the AhR is blocked the mice eat the same number of calories.  Obesity is not caused by overeating, it is a fuel partitioning disorder.

Furthermore, mice with a CYP1B1 gene knockout (they lack CYP1B1) have lower expression levels of SCD1 and the other lipogenic genes and are (somewhat) resistant to obesity.^​7​

Evidence That the AhR/CYP1A1/CYP1A2/CYP1B1 axis affects human obesity

Dioxin levels are directly associated with abdominal obesity.^​8​  AhR and CYP1B1 are highly expressed in blood cells of obese children compared to controls.^​9​  A gene polymorphism in CYP1A1 was associated with abdominal obesity in Egyptian women.^​10​  There was a direct correlation between BMI and intestinal levels of CYP1A2 in obese adults undergoing bariatric surgery.^​11​

Blocking the AhR cures obesity in mice

I first mentioned this in The SCD1 Theory of Obesity Part 2.  This was the experiment:^​12​

Three groups of mice were made fat on a Western diet while control (lean) mice ate regular chow food.  The three groups of mice either: 1) remained on the Western diet, 2) which switched back to the control diet or 3) remained on the Western diet but with a pharmaceutical inhibitor of the AhR.

The mice kept on the Western diet had massively increased SCD1 levels and became the fattest.  The mice switched to the control diet still had massively increased SCD1 levels and remained obese compared to controls.  The mice with the AhR blocked on the Western diet had SCD1 levels reduced to control levels and immediately returned to the weight of lean controls.

The other thing this experiment showed is that the level of an enzyme called phospholipase A2 (Pla2g4a) was greatly increased in Western Diet fed mice but that the increase was eliminated by blocking the AhR.  The job of Pla2g4a is to release arachidonic acid from membranes so that it can get oxidized by CYP1B1 into keys to turn on PPAR gamma.  So stimulating the AhR both mobilizes and oxidizes PUFA.

The AhR is Stimulated in the liver by oxidized LDL

When you consume PUFA, your liver packs it into particles called VLDL and releases the VLDL into the bloodstream.  Cells “eat” the fat in the VLDL and as they become smaller, they are called LDL, which many of you know of as “bad cholesterol”.  The LDL tend to collect PUFA and if this PUFA oxidizes the LDL becomes oxidized LDL (oxLDL).  oxLDL in the bloodstream signals TLR4, a receptor in the outer membrane of liver cells, which activates the AhR through a pathway involving NF-kB and an enzyme called IDO1.^​13​

IDO1 converts the amino acid tryptophan into something called kynurenine, which directly activates the AhR. The AhR ALSO activates IDO1, thus creating a positive feedback loop.  The AhR activates IDO1 which makes kynurenine, which activates the AhR.

The Full Pathway from PUFA to torpor

You eat PUFA, your liver packs it into VLDL, which ultimately creates oxLDL.  The oxLDL stimulates the AhR in your liver.  The AhR upregulates the cytochrome P450 enzymes and  phospholipase A2, which create the specific oxidized PUFA that is the key to turning on PPAR gamma.  PPAR gamma turns on the lipogenic genes SCD1, ACC, FASN, ELOVL6 and the others.  Obesity and torpor ensue.

Dealing with the AhR

There may be some good news here for humans.  This 2016 paper^​14​ suggests that a genetic change in the AhR that differentiates us from neanderthals and other primates makes the human AhR much less inducible by xenobiotics such as dioxins.  The theory is that as we learned to use fire to cook our food, we adapted to constant exposure to smoke and charred meat by evolving a less active AhR.  This 2020 paper^​15​, however, refutes that finding.

Depressingly, for those of us who are not exposed to dioxins in the workplace, our main source is animal fat.  The dioxins from industrial products are widespread and occur in small amounts in soil and plants and bio-accumulate in animal fat.  According to the EPA, typical American consumption is 119 picograms, which they claim is a safe level. 

Other potential sources of compounds that would activate the AhR include charred food, cigarette smoke, auto exhaust.  Basically anything that’s on fire.  Probably also fryer oil.

Interestingly, resveratrol blocks the activation of the AhR.^​16​  I’ve talked about Resveratrol on this site before as something that downregulates SCD1.  Perhaps the mechanism by which this works is its suppression of AhR.

Check back in, the next article will show how to REALLY combat the effects of the AhR.