It’s rare to find a scientific paper whose RESULTS are hilarious. Sometimes the authors conclusions are hilarious. If you’ve lived through the last 30 years of articles about the best sources of antioxidants and how to avoid oxidative stress, though, the actual findings of this study1 will certainly seem ironic, if not hilarious.
I’ve written about Nrf2 before. It’s a critical transcription factor in controlling antioxidant defense. For instance, when Nrf2 is activated by Reactive Oxygen Species (ROS), it upregulates the production of glutathione, the body’s “master antioxidant”. This is the body’s first line of defense against oxidative stress.
But what happens if you remove the Nrf2 gene from a mouse?
- Cellular buildup of hydrogen peroxide, AKA “Oxidative Stress”
- A large increase in Ucp1, AKA Mitochondrial Uncoupling
- Increased Metabolic rate
- Resistance to Obesity
- Improved glycemic control
- Lowered fasting insulin
Come on….. It’s funny!!
But of course the mice were suffering in all sorts of ways due to the massive oxidative stress. Right?!
According to the authors, “Mice lacking the Nrf2 gene demonstrate no obvious outward defects”.
They do seem to have some long term bad effects, including increased susceptibility to certain toxins and carcinogens. But mostly, they are normal mice with a souped up metabolic rate.
What happens if we culture some cells from these mice? Normal cell culture but with much higher oxygen consumption, AKA higher metabolic rate. And if we add some powerful antioxidants to the tissue culture? The oxygen consumption, AKA metabolic rate, drops.
Bro, My Mind Is Blown, Everything Is Backwards, How Can I Go On?
It’s going to be OK.
The body often has redundant ways of coping with problems. Glutathione is the first line of defense against oxidative stress. But Ucp1 is the second line of defense. The production of ROS is an inevitable result of oxidative phosphorylation, which is the broad term for how the mitochondria uses oxygen to convert the chemical energy in a fat or carbohydrate to ATP.
The mitochondria is like a battery. The electron transport chain pumps protons to the outside of the inner mitochondrial membrane, meaning that the area outside of the mitochondria has a positive charge and the area inside of the mitochondria has a negative charge, just like the two terminals of a battery. The mitochondria uses this voltage difference to do work. Complex V uses this voltage difference to convert ADP to ATP. ATP is the bodies primary fuel and is used to move muscles, for instance.
This process creates ROS. Normally, the ROS would activate Nrf2, which will increase glutathione, which will mop up the ROS. But if Nrf2 doesn’t exist, the ROS just build up as hydrogen peroxide. The cells response is to increase UCP1. UCP1 “uncouples” the mitochondria, meaning that it allows the protons to “leak” back through the inner mitochondrial membrane. This releases energy as heat, as opposed to using energy to do “work”: moving a muscle.
The ability to simply let the protons flow back through the membrane reduces the voltage differential across the inner mitochondrial membrane. When the voltage differential is low, it’s easier to pump protons across the membrane by the enzymes in the electron transport chain. When the voltage differential is low, far less ROS are produced. The cell is saved from massive oxidative stress. It IS under oxidative stress, but it’s not that bad. Maybe there’s twice as much hydrogen peroxide around, but hydrogen peroxide isn’t that reactive. The cell can deal with it.
The difference between the two scenarios – ROS being dealt with by glutathione vs. ROS being dealt with by UCP1 – is that with glutathione, metabolism is very efficient. Very little chemical energy is “wasted” as heat.
When UCP1 levels are high, the metabolism becomes very inefficient. You are losing energy that could be used to move muscles by just burning it off as heat.
Evolutionarily, inefficient metabolism is a BAD idea and would be selected against. Why would you want to waste hard earned calories as heat?! If you’re a modern fat person, the tables are turned. Maybe you want to be inefficient.
A surge of ROS in your mitochondria will get you there.
- 1.Schneider K, Valdez J, Nguyen J, et al. Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2). Journal of Biological Chemistry. Published online April 2016:7754-7766. doi:10.1074/jbc.m115.673756