Insulin resistance (13) NAC and UCP3

I think we just need to tidy up the effect of NAC on bodyweight before we go on to look at vitamin E in a related role.

The effect of NAC on total body weight of chow fed mice is zero. We have this paper from 2022

Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling

which includes this highly convincing graph:

This is a reiteration of the findings in this (not cited!) 2016 paper

N-acetylcysteine Protects Mice from High Fat Diet-induced Metabolic Disorders

which is where I started this thread because I was interested in whether the drop in ROS generation mediated by uncoupling could be recapitulated using an antioxidant to reduce ROS rather than UCPs themselves. The answer is clearly both yes and no.

If we look at the weight graph here:

and remove all data points except the mice on chow and the mice on chow plus NAC we get this:

I think it is reasonable to suggest thet NAC does nothing to the body weight of healthy mice on chow. Except this is not the case for body composition. Here we have, from the same figure, lean and adipose masses of all groups

As always, we have to look slightly deeper than total body weight. In this latter paper we do have an assessment of both lean mass and total adipose mass, shown here for the chow groups only: 

where, on a group size of five, we do have a statistically significant reduction in total adipose mass. It's probably real. If we reverse engineer the figure we get, in crude approximation, 15% body fat in the chow only mice:

and for the chow plus NAC group we have 7% body fat:

Ignoring the p < 0.05, I think most people could identify which group of people at any gym had 15% body fat compared to a similar weight group but with 7% body fat.

You might, or might not, be surprised that the lower body fat group were scarfing more (ns) calories per day than the chunkier group. As a dietician looking at humans you would just assume the fatter folks were lying about food intake, as dieticians do (sic), but in mice you can weigh the food.

Of course the answer is in mild uncoupling. Here are the data for UCP1 in the chow-only fed mice, a trivial increase, also ns. This is not about bulk thermogenesis:

However this is not the case for UCP3. Here the p value is small and the effect large:

This suggests that the increase in gene expression for UCP3 is doing something different to the routine function of UCP1. Undoubtedly UCP3 is not UCP1. A superficial glance at even the abstract of

Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate

shows that activation of UCP3 has far more to do with metabolism control than heat generation. A flavour comes from another superficial glance at

Muscle-UCP3 in the regulation of energy metabolism

This latter paper even suggests that UCP3 in muscle (in this case) might be related to control of ROS production. Well, whodathunkit? The authors seem unable to comprehend that all of the numerous "effects" of UCP3 activation can be most simply attributed to a decrease in insulin signalling.

So why does NAC increase UCP3 gene expression in the BAT of mice on NAC, as it does? Probably because it increases UCP3 gene expression everywhere in the mouse, although this wasn't checked.

Let's go back to what is happening on the ROS basis in mice eating chow with NAC.

Cells should uptake energy substrate until "full" and then refuse excess. NAC removes the ROS that signal this "fullness". Substrate continues to enter the cell, a process exactly analogous to the failure to resistance to insulin's signal resulting from the inadequate ROS generation due to LA's low FADH2 supply.

Results should be increased lipid storage and a pathological increased supply of reducing equivalents in to the ETC.

This provides the potential for very high delta psi and activating UCP3 appears to be an adaptation to avoid this. This is a very basic hypercaloric situation. Uncoupling is protective.

Under fasting conditions, ie under low (but not zero) insulin levels, NAC removes the small component of insulin signalling still present in adipocytes so allowing more FFA release than is appropriate. Again, excess FFA delivery supplies excess reducing equivalents to the ETC with potentially damaging high delta psi generation. Again, uncoupling is protective.

So NAC over distends adipocytes in the fed state due to suppressing physiological insulin resistance, comparable to linoleic acid's effect. Under fasting conditions NAC allows excess lipolysis, giving weight loss from shrinking those distended adipocytes. In many ways this is analogous to the blunting of insulin signalling by metformin.

The end result will depend on the dose rate of NAC and the nature of the chow (or high "fat" diet) being fed.

The fundamental point is that scavenging ROS and avoiding weight gain does NOT imply that weight gain is caused by excess ROS. Weight gain is caused by *inadequate* ROS post prandially which can be offset by increased lipolysis during fasting. Same drug, same action, different conditions.

A nice paradox unless viewed from the ROS perspective.

Peter