The ROS Theory of Obesity

AKA The Layperson’s Guide to Hyperlipid

This series is going to be exploring the root cause of obesity and how energy balance is controlled at a cellular level. My thinking on this subject has been heavily influenced by Peter at Hyperlipid and his protons theory. His writing is dense, technical and full of acronyms. I will try my best to explain things in plain English. Additionally, I will be expanding his very low-level theory to look more speculatively around the world and ask, “Does this make sense given what we see in different populations?”

If you haven’t already, now would be a good time to read the Intro to Oxidation series to become comfortable with terms like ROS and superoxide.

In my opinion, a theory about obesity should explain, at least partially, all of the different cases that we can see in human populations, except perhaps in the case of rare genetic mutations. When I look around the world – both the current world and past examples that are well-chronicled – I see a lot of different populations with very different diets where obesity is rare.

A Three Country Study

A quick look at China, France and the US sets up our case study. Chinese peasants in the early 1980’s ate a VERY low fat diet where 80% or more of their calories came from white rice – a refined carbohydrate – and they were slim and lacked signs of diabetes. At the same time, the average Frenchman in 1970 – when France’s economy had had 25 years to recover from WWII – ate a very high fat diet with dairy fat as the predominant fat source and were slim and lacked signs of diabetes. Modern Americans eat a diet which looks a lot like the French diet in 1970 in terms of macronutrient composition – Fat, Carbohydrate and Protein – but obesity and diabetes are commonplace. Why?

A theory about obesity should be able to explain all three scenarios, or at least explain one or more of them without contradicting the others. A lot of different theories have been proposed but none are very satisfactory.

TheoryReality
Low Fat diets prevent obesityLow fat diets in places such as China gave rise to the idea that a low fat diet could prevent obesity. But this theory can’t explain why the French in 1970 were also slim or why low fat dietary trials in the US have largely failed.
Low Carbohydrate diets prevent ObesityLow carbohydrate and ketogenic diets have become very popular weight loss diets and have, if anything, been more effective than low fat diets for weight loss, but if carbohydrates cause obesity then why were the Chinese in the 80s and the French in the 70s so slim?
Obesity is caused by Food RewardA popular theory is that high reward processed foods overwhelm humans ability to limit their caloric intake. Delicious (ie rewarding) processed foods cause us to overeat, leading to obesity and diabetes. But the French diet in 1970 contained large amounts of white flour, sugar, butter, cheese and meat served with wine. Is the modern American diet REALLY more palatable than that?
Mediterranean Diet is bestAccording to the Mayo Clinic. “The foundation of the Mediterranean diet is vegetables, fruits, herbs, nuts, beans and whole grains. Meals are built around these plant-based foods. Moderate amounts of dairy, poultry and eggs are also central to the Mediterranean Diet, as is seafood. In contrast, red meat is eaten only occasionally.” But the Chinese stayed slim on a diet of mainly refined carbohydrates and the french stayed slim on a diet of white flour, white sugar, meat and full fat dairy. Yes, both places also consumed reasonable amounts of vegetables (actually, in some places in China they ate very little vegetables) but nothing close to what is described in the Mediterranean diet.

The ROS Theory of Obesity

The ROS theory says that energy balance is largely controlled by the interplay between ROS (Reactive Oxygen Species) produced in the mitochondria and hypothalamus and hormones like insulin and leptin. In this theory saturated fat – both from the diet and produced in the body from carbohydrate – acts as a molecular switch that by creating ROS in the mitochondria toggles the metabolism between running on glucose and running on fat. Saturated fat provides metabolic flexibility – the ability to tap into fat stores when available.

ROS, generated from saturated fat metabolism (oxidation), is the signal that prevents cells from switching from fat metabolism to glucose metabolism. They do this by creating a short term condition of physiological insulin resistance which prevents cells from responding to insulin – and therefore switching over to glucose burning – as long as the cells are still burning saturated fat.

You read that correctly. I am arguing that everything we think we know about obesity is exactly backwards. Instead of choosing unsaturated fats to avoid free radical formation which leads to insulin resistance we should be seeking out long chain saturated fats which cause free radical formation which leads to physiological insulin resistance.

The ROS theory is the first theory of obesity I’ve seen that can explain the situation in China, France and the US. In addition, it explains why ketogenic diets work and why low fat diets, which seem to work well in China, often fail in America.

We’re going to look at the molecular mechanism by which saturated fat metabolism creates ROS, how ROS disables insulin signalling, how that signal effects energy supply in the blood after a meal and we’ll look at studies supporting this theory in both mice and humans.

The whole story starts at the Coenzyme Q bottleneck in the electron transport chain of the inner mitochondrial membrane.

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