Random musings on uncoupling (5) Vintage 2,4-dinitrophenol

Thinking about uncoupling leads to the idea that it is wasteful if it occurs in excess of that needed for useful thermogenesis. Being energetically wasteful on a fixed calorie input means you do not have adequate calories left for your metabolism (though you might cut a few metabolic corners) so you should be hungry in proportion to the extra calories-out as heat. On a non restricted diet you should just eat more.

When I started thinking about the activation of uncoupling proteins by linoleic acid and its derivatives it seemed logical to have a look at the metabolic effects of other mechanisms of uncoupling, the best known of which is 2,4-dinitrophenol (DNT). It is, at first glance, a much simpler situation than that of LA because there is no feature of its metabolic effects which might promote excess caloric storage.
All it does is uncouple respiration and turn food, mostly fat, in to heat.

A more nuanced reflection would be that such a huge calories-out might be the equivalent to climbing Ben Nevis several times a day. Which ought to make you hungry.

While high dose DNP undoubtedly does make you hungry, the increase in hunger can be relatively easily offset by mild stimulators of lipolysis such as caffeine and/or sympathomimetics.

It would take more than a couple of cups of coffee to get you up and down Ben Nevis four times in a day.

So DNP not only increases calories-out, it must also be increasing access to calories-stored, allowing them to become calories-in so as to convert them to calories-out without excessive hunger.

Reverse electron transport, needed to generate the ROS which are essential to maintain insulin signalling, is highly dependent on the mitochondrial membrane potential. The core function of DNP is to lower that membrane potential and it should lower ROS generation and so blunt insulin signalling.

The effect is non specific, it doesn't matter where the FADH2 and NADH inputs are coming from, if membrane potential is artificially lowered, all of insulin's signalling will be reduced.

Not eliminated, but enough to access adipose tissue's stored fat in proportion to the blunting of insulin's action. Clearly there is no obvious need for the decrease in insulin signalling to exactly offset the increased heat generation. It happens to be close and a bit of caffeine appears to match things up nicely.

This is how I view the high dose rate fat loss facilitating effect of DNP. It still seems to be used as such in cultures where rapid loss of residual fat is required to get the perfect physique for a competitive edge in physical culture circles. Risk of death is of little concern, after all, exogenous insulin is used to bulk up muscle before cutting fat with DNP, if you are dedicated enough.

There are currently attempts to rehabilitate low dose/sustained release DNP as a useful drug. This review was written by a researcher heavily committed to such a drug development project. He's biased, of course, but that doesn't stop him being correct:

2,4 Dinitrophenol as Medicine

In some ways I approve, getting rid of people's fatty liver for them, or even correcting full blown NASH, is a Good Thing. Except I'm uncomfortable with the concept of applying a sticking plaster to metabolic syndrome and then waiting to see what other catastrophes turn up further down the road. After all, you only have metabolic syndrome because you have chronic linoleic acid intoxication.

However this might be quite a good sticking plaster, as sticking plasters go.

Peter