PUFA as an obesogen; How Seed Oils Cause Reductive Stress, Part VI

Obesogens are environmental toxins that make you fat. A commonality among them is that they activate receptors such as hormone receptors, androgen receptors, and perhaps most importantly, receptors in the nuclear receptor superfamily. Of course, if certain chemicals can make you fat, you have to really question the calories-in-calories-out theory of obesity. Certain chemicals can make you fat.

Classic examples of obesogens​1–5​:

Rosaglitazone – a pharmaceutical used to activate nuclear receptor PPAR gamma. It makes you insulin sensitive by forcing your adipose tissue to store blood glucose as fat.
Tributyltin – a dual PPAR gamma/Retinoid X Receptor (RXR) activator that is found in certain marine paints. PPAR gamma is the master regulator of adiposity. Activated PPAR gamma only works when its binding partner RXR is ALSO activated. This one activates both and causes obesity.
Bisphenol A (BPA) – a compound found in plastics that activates the nuclear receptors PPAR gamma, and the Steroid X Receptor (SXR, AKA the Pregnane X Receptor (PXR))
PFOA is in consumer products and can be found in the blood of most Americans. Much like PUFA, PFOA is a potent stimulator of PPAR alpha. PFOA blood levels are HIGHLY correlated with levels of obesity.
Dioxins, also known as forever chemicals due to their 400 year half lives in the environment, are in out drinking water, beef, fish and in most other foods. They are strong activators of the Aryl Hydrocarbon Receptor (AhR), another member of the nuclear receptor superfamily. The Hudson river is contaminated with PCBs a family of well known dioxins.

The nuclear receptor superfamily members have several things in common​6–12​:

They are involved in detoxification of organic pollutants, which is why they are activated by these compounds in the first place. To perform their role in detoxification, they upregulate enzymes called cytochrome p450s. These enzymes oxidize the toxins to break them down, but they also oxidize PUFA.
Most of these receptors can be activated by the very oxylipins that are created when the cytochrome p450 enzymes (and other enzymes) oxidize PUFA. This is a classic positive feedback loop.
Most of these receptors activate NAD+ dependent enzymes that reduce NAD+ levels. Often this is CD38, but in the case of the AhR, it is an enzyme called PARP.

Omega-6 and omega-3 oxylipins are implicated in soybean oil-induced obesity in mice

Let’s consider the findings of this paper keeping in mind the idea of PUFA as obesogens that stimulate cytochrome p450s, create oxylipins and reduce NAD+. Here are the bodyweights of mice fed a lowfat diet (Viv – grey), a diet with hydrogenated coconut oil (CO – blue), a diet with more MUFA (PL+CO – pink) and a diet with more PUFA as a 50:50 mix of coconut oil with soybean oil (SO+CO – orange). As you can see, the coconut oil fed mice are the leanest ones who were given a high fat diet and the soybean oil fed ones are the fattest.

As we’d expect, there is a direct relationship between fat unsaturation and obesity. MUFA fed mice are fatter than SFA fed mice. PUFA fed mice are fatter than MUFA fed mice.

There are significant effects of soybean oil compared to coconut oil on activation of nuclear receptor family members as we can see by the changes in regulation of cytochrome p450 enzymes. Cyp3a41a is upregulated. The Cyp3a (cytochrome P450 3a) family is primarily controlled by the SXR​13​. We also see downregulation of Cyp4a12a. The Cyp4a family is primarily controlled by PPAR alpha. This pattern suggests that soybean oil is activating the SXR and de-activating PPAR alpha (even though it is a known PPAR alpha activator, it’s complicated).

The authors of the paper spend a lot of time talking about the relationship between the weight gain in soybean oil fed animals with the oxylipins 9,10 EpODE, 15,16 EpODE, 9,10 EpOME and 12,13 EpOME.  Which is fair, these epoxides were all upregulated by soybean oil, correlate with levels of obesity and are known or probable PPAR gamma activators.

Still, my eye couldn’t help but be drawn to the upregulation of 12-HETE by soybean oil in this “MAP” of the findings. Green dots mean “higher in animals fed soybean oil compared to those fed MUFA”.

12-HETE is a known strong activator of BOTH PPAR gamma​8​ and the AhR​14​.  PPAR gamma upregulates SCD1​15​ and the NAD+ dependent enzyme CD38​11​.  The AhR upregulates SCD1​16​ and the NAD+ dependent enzyme PARP​17​

SCD1, CD38 and PARP all decrease available levels of NAD+, bringing the metabolic rate to a crawl and increasing acetyl-CoA levels once again. As I’ve already mentioned, PPAR gamma activators and AhR activators are both known obesogens, as are those of the SXR. What better way to encourage fat storage than to upregulate lipogenic enzymes while at the same time depressing NAD+ levels?

We can say that PUFA is acting like an (is an?) obesogen by stimulating multiple nuclear receptors. The mice given the soybean oil DID get the fattest….

Torpor Time

None of this is pathology.  This is actually a beautiful example of biological regulation.  Consider once again the hibernating animal.  Its biological imperative is to store fat for winter once the signal comes.  The signal is the ripening of acorns, which introduce significant MUFA and PUFA into the diet.  The response to the unsaturated fats is multi-layered and self-reinforcing, ensuring the body stores sufficient fat.

Level 1:  The MUFA and PUFA in the acorns cause a slowdown in the mitochondria by flooding the mitochondria with fat and reducing production of NAD+ via the superoxide/glutathione reductase/NNT pathway.  The slowdown in metabolic rate leads to a buildup of acetyl-CoA, which activates lipogenic enzymes PPAR gamma and SREBP-1c and deactivates mitochondrial enzymes involved in metabolism, adding to the slowdown.  All of this is a direct mitochondrial effect of unsaturated fats.

Level 2:  The PUFA in the acorns act as obesogens, having a dramatic effect on nuclear receptor signaling.  It is unclear what the exact chain of events is, but the SXR is activated as are presumably PPAR gamma and the AhR, at least.  PPAR gamma and the AhR upregulate CD38 and PARP, respectively, lowering NAD+ levels even further.  Low NAD+ levels lead to rising acetyl-CoA levels and increasing acetylation of both lipogenic transcription factors (activating them) and mitochondrial enzymes (deactivating them).  You see how the unburnt fuel is the very thing that triggers fat storage rather than fat burning?

Level 3:  The steadily increasing activation level of lipogenic enzymes lead to a progressive rise in SCD1 levels.  SCD1 is upregulated by both PPAR gamma and SREBP-1c, which are directly activated by rising acetyl-CoA levels.  SCD1 unsaturates your body fat and when it’s fully activated it limits your ability to generate NAD+ through the superoxide/Glutathione Reductase/NNT pathway, leading to increased acetyl-CoA levels.  Hibernating animals and obese humans are full of MUFA from SCD1

The end result of this is a progressive increase in SCD1 levels and mitochondrial acetylation levels as obesity onsets.

Obese children have dramatically elevated acetylation levels of mitochondrial enzymes.
The change in acetylation levels of mitochondrial enzymes of hibernating animals throughout the year. The levels peak as they enter torpor.
There is near perfect correlation betweeen BMI and SCD1 levels in human muscle tissue.


This concludes my series on how seed oils cause reductive stress.  In part one we saw that mitochondria need proper oxygenation to burn cleanly.  WIthout that, a flooded engine leads to rising levels of unburnt fuel including acetyl-CoA.  In part two we looked at the superoxide/Glutathione Reductase/NNT pathway that ensures proper fuel oxygenation when we’re burning saturated fat but not when we burn seed oils.  Part three detailed how rising acetyl-CoA levels activate lipogenic enzymes.  Activated lipogenic enzymes represent a choice by the organism to store fat even if it doesn’t eat more calories.  Part four detailed a strange behavior of seed oils – they drive so much reductive stress that lipogenic enzymes are rapidly turned on and they are rebuilt as saturated fatPart five demonstrated how in the very short term, seed oils cause reductive stress in lean humans, causing them to behave metabolically like obese humans.

This last article showcases how oxidized PUFA act as activators of nuclear receptors which are known obesogens.  Not only that, they are also oxidized by the cytochrome p450 enzymes that are upregulated by the nuclear receptors.  This is a positive feedback loop ending in fat mice who ate soybean oil.

The whole series of events from ingestion of PUFA to obesity is a series of self-reinforcing control loops.  When the animal chooses to fatten up by eating PUFA, it is the prerogative of the organism to make sure this happens.

ONE LAST NOTE:  Some in this space have suggested that the effects of seed oils I am attributing to a change in mitochondrial dynamics are actually brought about by a rise in damaging oxylipins like 4-HNE.  I believe that 4-HNE is another damaging element of PUFA consumption, but I didn’t feel the need to bring them up here since the dynamics I’m talking about can be largely explained without them IMO and  Tucker Goodrich covers this topic well over at his blog Yelling Stop.

I’ve spent quite a bit of time examining in detail the effects of PUFA on mitochondrial dynamics.  Next up, we’re going to look at how to break out of this self-reinforcing cycle!  Probably after a brief solstice break, right after the 4th of July.  Stay tuned!

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