Random musings on uncoupling (1)

I thought I'd just take a break from trying to find any studies where sucrose-in-chow causes obesity in the absence of greater than 8% of calories as linoleic acid. That's becoming rather frustrating but is turning up some interesting studies on uncoupling and PUFA along the way.

So just for this post I thought I'd get even more speculative than normal about uncoupling.

Thermogenesis. Thermogenesis makes you hungry. That is not a completely intuitive statement.

It's easiest if we start with a food source which generates heat without utilising uncoupling because there are far less variables to think about. So think protein. Deconstructing a protein chain, processing amino acids to their core constituent energetic compounds such as pyruvate, glutamate etc requires energy and this energy shows up as heat.

Let's say 1000kcal of protein generates 300kcal of heat. I've no idea of (or interest in) the exact value, I just know you can warm a hypothermic patient post operatively using an IV amino acid infusion.

So if you are used to eating 2000kcal of fat a day to run your metabolism, you metabolism requires 2000kcal, tightly controlled. Let's also imagine you live in a thermoneutral environment and so are not muddying the water with (usually necessary) thermogenesis to maintain your body temperature.

If you swap your 2000kcal of fat for 1000kcal of fat plus 1000kcal of protein things change. The 1000kcal of protein provides 700kcal of usable energy and 300kcal of waste heat, which you don't need as you are in a thermoneutral environment.

So you get hot and uncomfortable and have a 300kcal deficit. You cannot run your metabolism of 1700kcal, you need 2000kcal. The hypothalamus notices this 300kcal deficit. What would you do? You would feel hungry and eat enough extra food to ensure that you actually get the 2000kcal you need for metabolism, tolerating the excess heat generation as an unwanted side effect. You would stay weight stable, eat a little extra to hunger and be sweaty.

Forced overfeeding is equally straightforward. You eat too much, uncouple, lose heat and hope you don't really live in a theroneutral environment.

Next is what happens under spontaneous eating but including more than 8% of calories as linoleic acid in your diet.

Here my hypothesis is that excess calories are available, the cell fills up and poorly-opposed insulin allows more calories to enter and for those calories to be sequestered out of the way as lipid (and probably glycogen too). From the cellular point of view energy status is fine (not overloaded) so long as the excess calories entering are being sequestered away from metabolism. The hypothalamus might perceive too few calories in the arterial blood in direct proportion to those being lost into storage in the periphery. So you eat more.

The next step in thinking is 2,4-dinotrophenol. This is a classical uncoupler and probably the most effective weight loss drug, particularly for fat loss, ever marketed. Sadly the therapeutic margin is narrow, unpredictable and can change suddenly.

High dose rate, rapid weigh loss DNP administration uncouples respiration to the point of ATP reduction and massive heat generation. AMPK is activated by the consequences of the fall in ATP, ensuring effective fat oxidation. With a marked fall in mitochondrial membrane potential there is going to be a cessation of reverse electron transport and the mitochondrial component of the ROS generation essential to maintain insulin signalling will collapse. At this point calories will be entering the cell through AMPK facilitated GLUT4s (and probably CD36s as well) and will not be diverted to storage but used for a combination of running metabolism plus extra calories equal to those lost as heat.

I understand from reading around a little that DNP does, indeed, make you hungry. The calories pouring though the mitochondria are coming from fat primarily and if the fat supply cannot keep up with the uncoupling-augmented metabolic needs then blood energy content will fall and the hypothalamus will notice. Also interesting is the use of drugs such as caffeine and ephedrine to control that hunger, both of which are reputed to work. They increase basal and sympathomimetic induced lipolysis, supply more fat and so control the hunger. So the loss of fat from adipocytes due to failed insulin signalling cannot quite keep up with the increased metabolic heat production without a little help. Not surprising because the shrinkage of adipocytes is from a failure of insulin signalling to facilitate fatty acid uptake combined with unopposed basal/sympathetic lipolysis. Neither is directly related to the huge loss of calories from unrestrained uncoupling. It surprises me a little that the supply and demand are so closely matched in such a complex system, especially with a major spanner dropped in to the works.

Which just leaves us with PUFA. These appear to facilitate uncoupling in proportion to the amount present in the diet, even on a meal by meal basis. My mental image for this phenomenon is that, intrinsically, PUFA allow too many calories in to a cell if insulin is the facilitating hormone. The more pronounced this effect, the more the need for uncoupling.

Modest excess, say over 8% of the diet by calories, works by the standard ROS/Protons concept of sequestration of excess calories. But you can only sequester so many excess calories and very high percentages of PUFA have the potential to overwhelm the system. We are talking 35% or over for uncoupling to predominate, but I think this might be a linear effect which is over-shaddowed by the ROS effect at lower concentrations but comes to dominate at very high concentrations.

At these very high levels of uncoupling the body is in caloric deficit because it is actually losing the calories as heat. It is metabolically the equivalent of the hunger of a high fat (10-30% PUFA) diet but does not involve the distention of adipocytes to achieve it. The degree of hunger would be in proportion to the deficit between lipolysis and heat loss via uncoupling and would require (not allow) a few extra calories to be eaten.

EDIT: This last section is poor logic. It might be worth a post to clarify or just a an edit to correct. I'm thinking about it.  I'll take it out and put a more considered discussion up as a follow on post. END EDIT.

Peter