Protons (74) Arne Astrup and the formerly obese

I have a soft spot for Arne Astrup. Back in the days of the depths of the Danish fat taxation stupidity, he was one of the voices of reason speaking out against the tax. It was a near miss for sanity. Academics have since argued that the tax was repealed too soon (and the sugar tax never got started) and that it was actually "working", at least among those who couldn't hop over the border to buy their (Danish?) butter in Germany. Had it been allowed to continue to "work" we might have successfully forced a whole nation to avoid fat, especially saturated fat. Where might that have led? If you wish to compose the answer on a postage stamp it is just three letters long, which will fit neatly on to even the smallest stamp.

Anyhoo. People may have noticed that I like this paper from the Astrup led lab

Fat metabolism in formerly obese women

mostly because Table 3 confirms all of my biases by showing formerly obese women are exquisitely insulin sensitive, which is pure Protons:

The rest of the paper is more difficult.

The formerly obese are, as expected, only deriving around 35% of their energy from fat oxidation at time zero on the graph below while the never-obese controls are deriving just under 80% of their energy needs from lipid oxidation, time zero again. These values are while sitting still on a bicycle ergonometer, after an over night fast. Not quite basal metabolic rate or resting energy expenditure but pretty close:

It is also worth noting that performing exercise at 50% of VO2 max (previously individually measured) completely normalises energy production derived from fat oxidation. Those are time points 15-60min. All we need here is for AMPK to instigate oxidation of the fatty acids available while suppressing their formation. Then the pathological insulin sensitivity is bypassed. There are several posts possible on AMPK but again, here is not the place to explore the control of insulin signalling by AMPK and vice versa. Both happen.

Finally, the really strange thing is that these formerly obese women have modestly *elevated* FFAs, both at rest and throughout exercise, consistently around 300µmol/l greater than controls.  If the formerly obese have all this extra lipid available, why don't they oxidise it?

We can say, quite conclusively, that these FO women have normal electron transport chains. Under exercise they oxidise lipids exactly as well as control women do. My assumption is that there has to be a signalling problem which is inhibiting fatty acid oxidation but can be over-ridden by AMPK activation.

We know, from a mass of rodent and human studies, that when you allow a subject access to carbohydrate food (or an OGTT) after an extended fast, they perform de novo lipogenesis, giving an RER > 1.0, for about an hour. The duration is interesting. Insulin-induced insulin resistance (which is complex and probably involves the glycerophosphate shuttle) usually comes in to effect at around about an hour in many models. This will reduce insulin signalling from its peak action under "hungry" conditions to a more moderate "fed" signal.

So peak insulin signalling after a fast, but before establishment of some physiological limitation, is a potential major driver of de novo lipogenesis with storage as triglyceride and, as we shall see, an effective inhibitor of fat oxidation.

Mechanistically we have to look briefly at the Randle Cycle.

Two of the many actions of insulin are to activate the pyruvate dehydrogenase complex and the acetyl-CoA carboxylase complex. This generates malonyl-CoA which inhibits CPT1 mediated transport of fatty acids in to mitochondria. Hence FFAs are available but not oxidised. But there is no problem with the mitochondrial ETC itself, all that is needed is for the insulin signal to be reduced.

During that initial refeeding period both the RQ of >1.0 and the inability to oxidise lipid can be viewed as manifestations of marked insulin sensitivity. Carbohydrate uptake is enhanced by insulin and the products of this carbohydrate catabolism are diverted, by insulin, to metabolites which inhibit fat oxidation and away from the Krebs Cycle and the electron transport chain.

Aside: My interest is in ROS based control systems so I have tended to ignore such details. But here the downstream effects of excessive insulin signalling on the Randle Cycle do matter. My bad. End aside.

My premise is that obesity is cause by a pathological sensitivity to the hormone insulin, mediated by linoleic acid. If this is correct then we would expect pathological lipid synthesis/storage to be combined with an inhibition of fatty acid oxidation. The normal "one hour" of peak insulin sensitivity is extended or even becomes continuous by using linoleic acid as a significant energy source (pax uncoupling intakes).

Here we have the formerly obese who are, without a doubt, destined to become obese again in the future. We also have people with obese parents who are not yet obese themselves. Both show the accentuated insulin sensitivity in combination with depressed fatty acid oxidation, both at rest and post prandially. All that is required to do this is to allow insulin to continue to act at peak efficacy under conditions where a functional limitation should have been imposed. Linoleic acid replacing palmitate/stearate under the Protons hypothesis provides exactly this.

So, in Astrup's particular group of formerly obese subjects described in the current study, it has proved possible to have inhibited fatty acid oxidation with sufficient severity that it leads to elevated plasma FFAs, because they cannot be used for energy generation. All as a consequence of augmented insulin signalling.

This particular group of FO subjects do appear to be a rather extreme example. Other FO people assessed by Astrup's group in previous studies do not feature the elevated FFA or profoundly depressed fasting insulin aspects, though the inability to oxidise lipid to produce adequate energy is a consistent feature over many studies. I think this current group of women are probably outliers who give an insight in to mechanisms. That's good.

It's also clear that these formerly obese women have a metabolic rate under fasting conditions significantly lower than that of the never obese controls. This is not surprising. Fat oxidation is being largely inhibited by elevated malonyl-CoA and a significant portion of glucose is being diverted from energy production to form that malonyl-CoA and its derived and stored lipid.

The FO women's resting energy expenditure is 3.77kJ/min, ie 0.9kcal/min, 1296kcal/24h. Never obese women expend 4.88kJ/min at rest, 1.2kcal/min, 1728kcal/24h. Except of course the FO women are not oxidising fat, because they are unable to effectively oxidise FFAs. They are using glucose.

So they are 461kcal/24h "hungrier" than never obese controls and are running on limited supplies of glucose from glycogen. The obvious solution is to access more glucose, which insulin has actively locked in to the liver/muscle stores of glycogen.

Traditionally this is solved in the real world by raiding the fridge at 3am. For something sweet. Much of which will be diverted to storage.

Weight gain.

It happens.

Peter