Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
It is a great resource on many levels, provided you completely ignore any of the paper's conclusions.
The most entertaining quote is this one from the control intervention period which involved the iv injection of a very small dose of lipopolysaccharide to induce insulin resistance. As the authors say:
"Only endotoxin administration led to mild flulike symptoms with a maximum after 3 h, while other interventions had no side effects."
"Only endotoxin administration led to mild flulike symptoms with a maximum after 3 h, while other interventions had no side effects."
What they didn't report was that the volunteers, after the endotoxin administration, came up with any spontaneous comment along the lines of:
"I could murder a steak now"
Almost certainly because it didn't happen.
I conclude that either a few hours of insulin resistance doesn't make you hungry or Nowotni is keeping shtum about the hunger generating effects of insulin resistance.
I struggle to identify inflammatory insulin resistance as a trigger for obesity. Even if it is chronically present. The last serious viral infection I had was probably in the late 1980s. If I recall correctly I lost 4kg in a weekend and only part of that was fluid loss. I wasn't hungry. I also went through a period of chronic inflammatory problems while I lived through mycoplasmal arthritis in the months soon after qualifying. I got through an awful lot of paracetamol before the medics got the diagnosis and subsequently I got through an awful lot of oxytetracycline at high dose to get it sorted out. No weight gain from inflammation though.
The endotoxin in the study caused the same degree of insulin resistance as ~900kcal of oral or iv soybean oil. But it provided no caloric input, so this insulin resistance is apparently not an obvious satiety signal.
And it's not pathology either.
Let's actually do some thinking about the advantages of insulin resistance during acute infection.
It's probably most illustrative to initially consider the insulin resistance of fasting. While this is often the situation during infection it is also a normal feature of simply not eating overnight. It is essential for survival, especially if fasting has to be extended.
The primary advantage of this aspect of insulin resistance is to spare glucose for the brain. While our brain can run perfectly well on ketones, these take time to develop and the default setting in modern agricultural society is to run your brain on glucose and leave daily ketosis to oddballs like myself and a few others.
So the ROS generation from FFA oxidation under fasting spares glucose for the brain, useful because the brain preferentially utilises glucose in modern times. Muscles and related tissues are very happy to run on fat and so resist insulin.
There is another part of physiology which is highly dependent on adequate calories from glucose for its optimal function and that is the immune system.
The case is laid out here
Metabolic syndrome and robustness tradeoffs
and here
Obviously both sets of authors have zero understanding of the causes of metabolic syndrome but have successfully linked the insulin resistance of starvation to maintaining brain function and the insulin resistance of infection to maintaining optimal immune function.
The second paper also throws in the insulin resistance of exercise, which I hadn't thought of, but makes sense.
Please, please, please bear in mind that NONE of these folks understand the cause of metabolic syndrome from the Protons perspective and so have no idea of why the previously adaptive trait of insulin resistance should now appear to be maladaptive. Modern life is suggested to allow "pathological" insulin resistance through a deficiency of mammoth-killing exercise and/or via a deficiency of starvation on bad hunting days. So they say.
Stop sniggering at the back!
So what *should* happen in infection is that adipocytes and hepatocytes release both FFAs and glucose to optimise immune function. Flooding the immune system with caloric substrate is pro-survival in infection or trauma.
At the same time all non immune essential cells should limit their caloric uptake, especially that of glucose, to their needs and no more. Predominantly from FFAs.
During the early evolution of organisms which have a recognisable immune system and separate organ systems for caloric storage all that would be needed is for evidence of tissue damage to trigger caloric substrate release to facilitate effective pathogen attack and/or tissue repair.
The simplest signal for this would be fragments of damaged tissue, ie 4-HNE, or pieces of damaged pathogen, ie LPS (fragments of the cell wall from gram negative bacteria). Or similar substances. A basic system would have the energy storage tissues "seeing" evidence of distant damage with a resultant generation of ROS in response. Those organisms which failed to do this failed to survive.
Because metabolic substrate is being flooded in to the circulation, use of the glucose component by tissues which can preferentially use fatty acids with their ROS generation should be limited. The ROS from FFA oxidation will automatically control caloric ingress to optimal for each insulin sensitive cell. The excess substrate, especially glucose to drive NADPH derived ROS generation through NOX enzymes, is then available to attack the pathogen and improve survival.
I suppose the next step to improve would be for immune cells involved in active duty at the site of damage to send a more reliable surrogate messenger and clearly tell the adipocytes/hepatocytes to respond decisively and release substrate without waiting to see how the untidy message of fragments of damage debris might work. So cytokines were developed as long distance messengers. I would hazard a guess that they might be derived from stabilised sections of proteins used in defence of integrity. Of course the same signalling molecules could be used to tell non involved insulin sensitive cells that a flood of emergency calories is on its way and better get resisting insulin now, in anticipation.
The next move is to have a sub population of immune cells actually sitting among adipocytes and hepatocytes, listening for cytokines, ready to act as local amplifiers of incoming signals. Their function would be to signal, via local cytokines and ROS, to adipocytes/hepatocytes to resist insulin, spill caloric substrate and gear up for battle.
There is nothing wrong with doing any of this. We can, with this perspective, regard the insulin resistance induced by inflammatory cytokines as the warning that a caloric flood is on its way, that that caloric flood is destined for the immune system, and it is now essential to enter excess calorie mode, ie resist insulin, in anticipation. I think of these higher level signals as a form of looking in to the future.
Although it might not be obvious initially, the sudden release of metabolic substrate in infection provides a surplus of energy availability at the cellular level despite anorexia. Exactly as fasting does. Running your metabolism on FFAs fundamentally generates ROS without needing insulin facilitated glucose uptake. Fasting, once metabolism is running of FFAs and ketones, is an energy replete situation at both the individual cell level and the central nervous system level. For modern glucose oxidisers the first three days might be hard.
What *is* wrong is for adipocytes (and, presumably, hepatocytes) to accumulate so much lipid that they die by catastrophic failure secondary to over distension. At which point all hell breaks lose within the local tissue to form highly inflammatory crown-like structures and to signal over long distances via cytokines that a disaster is happening. The pathologically augmented inflammatory signalling in adipose tissues is not causative of obesity. It is a response to individual adipocyte obesity. This is most obvious in the most insulin sensitive adipocytes, ie visceral/omental adipocytes. Which become "inflammed" first because they distend first, ie because they are the *most* insulin sensitive.
The modern maladaptive inflammatory problems of obesity all stem from the failure to limit insulin mediated distention of adipocytes (and probably hepatocytes).
It's not gluttony and sloth.
It's not failure to find food for a week or failure to attack a mammoth.
Linoleic acid is, of course, the primary problem which breaks the system.
Peter
PS There is a follow on in this paper
Effect of a prolonged low-dose lipopolysaccharide infusion on feed intake and metabolism in heifers
which suggests that in modern organisms that the release of FFAs and glucose under endotoxin exposure is now mediated by active lipolysis via sympathetic drive and lipolytic hormones. Not really surprising. Eukaryote evolution has had a couple of billion years to produce functional heifers.
Effect of a prolonged low-dose lipopolysaccharide infusion on feed intake and metabolism in heifers
which suggests that in modern organisms that the release of FFAs and glucose under endotoxin exposure is now mediated by active lipolysis via sympathetic drive and lipolytic hormones. Not really surprising. Eukaryote evolution has had a couple of billion years to produce functional heifers.
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