Insulin sensitivity makes you fat

TLDR: Excessive insulin sensitivity sets you up to become obese. Becoming obese makes you insulin resistant. Eventually excessive adipocyte size will induce systemic insulin resistance. Further weight gain is still possible given a diet which induces systemic hyperglycaemia combined with a pancreas of steel. Here we go.


I picked this paper up from Pubmed while looking for something else:

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

It's very interesting.

Over the years I have collected various models, mostly mouse/rat models, which generate obese, insulin resistant rodents.

These mostly involve damaging the hypothalamus in some way and letting the mice eat ad lib until they reach the desired level of obesity, with the associated insulin resistance. There is the ventromedial hypothalamic injury model

Molecular and metabolic changes in white adipose tissue of the rat during development of ventromedial hypothalamic obesity

The MSG injury model:

Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate (MSG) treated-rats

Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats

The gold thioglucose injury model:

Adiponectin expression is paradoxically increased in gold-thioglucose-induced obesity

What they all have in common is that the models are always more insulin sensitive in the first weeks after injury compared to the non-injured controls. This excess sensitivity persists until a certain level of obesity is achieved. As obesity increases so does systemic insulin resistance increase (a separate mechanism) until it overwhelms the excess insulin sensitivity and rate of weight gain markedly reduces. The model is now insulin resistant.

Inappropriate insulin sensitivity is what generates the obesity. Insulin resistance limits its progression.

Insulin resistance in adipocytes can, undoubtedly, occur but this is not a feature of the adipocytes in the early stages of obesity. They are insulin sensitive. Insulin acts easily. Adipocytes distend.

Back to the paper. It enrolled young, male, non-obese offspring of obese parents. Let's call them pre-obese. Sadly the paper is from 2004, it's now 2020, I would expect the "pre" prefix might nowadays be redundant. Here are the subject characteristics:

To me it is interesting that the pre-obese chaps were carrying more fat mass than the controls. There is a 1.7kg excess, statistically ns but the trend is there. You have to wonder how close to 0.05 the p value might have been.

Here are the fasting metabolic parameters for both groups:

Notice that the fasting insulin is lower in the group with higher fat mass, provided they have obese parents. It's also interesting that their fasting FFAs are higher than those of the folks with slim parents. This difference is also ns but the numbers after the +/- sign are standard deviations, not standard errors, so my guess these too are close to significance (for what that is worth). I also like the ns elevated trigs, I suspect related to repackaging the elevated fasting FFAs. Which are elevated due to increased adipocyte size allowing increased basal lipolysis. All speculation.

Next we have the insulin response to a quite pleasant sounding, mixed macro, highish fat meal:

The fasting insulin is the one from Table 2, p being 0.007 and for a large percentage of the post-meal eight hour period insulin stays significantly lower in the pre-obese group than in the normal-weight parent group. The pre-obese subjects are consistently more insulin sensitive.

Here is the FFA graph for the same eight hours:

Converting the FFA levels to real money terms it appears that the lean parent group had FFAs of 280micromol/l and the pre-obese people had 390micromol/l. I've already speculated that the elevated FFAs in the pre-obese group are from increased basal lipolysis, not insulin resistance. As soon as insulin is released after the meal FFA levels become identical for eight hours. I've not copied the trigs graph but the trend is for chylomicrons to be the same between groups for 4 hours and then lower in the pre-obese as insulin sequesters fat in adipocytes.

Which group will be metabolising most fat under hypoinsulinaemic, near-basal lipolytic conditions? Pre-obese have elevated fasting FFAs and they're oxidising more fat, 1150 vs 740mg/kg FFM/d,  ns but you can see the trend:

However, as soon as insulin rises fat oxidation drops because insulin sequesters fat in to adipocytes at levels way below those which translocate GLUT4s. It will also divert intracellular FFAs in to intracellular triglycerides. Lipid oxidation under insulin drops to 90mg/kg FFM x 8h compared to 163mg/kg FFM x 8h in the more normal individuals. Giving p less than 0.007.

BTW FFAs stay high in both groups because the meal was around 50% fat. I would predict that a high carbohydrate, low fat meal would have produced a marked drop in FFAs and a rise in RER, both more pronounced in the people with obese parents. No data on that one.

I do not think these pre-obese people have an injury to their hypothalamus. It is more likely the problem is with their adipocytes causing the excess insulin sensitivity.

I think we can ignore discussion comments about the influence of medium chain acyl CoA dehydrogenase variation as a red herring because the pre-obese folks are oxidising more fat under fasting conditions, ie when more lipid is available. The leptin receptor comment is lovely because we know that in mice with a complete leptin receptor deficiency that providing less than 5% of calories from PUFA is highly protective against obesity while providing 15% PUFA in the diet is grossly obesogenic (first link in the blog post). Clearly dietary fatty acid composition trumps even gross leptin signalling deficiency.

What were the diets like in the pre-obese participants? All we know from this study is that the ratio of PUFA:SFA was higher in the pre-obese people:

"The polyunsaturated to saturated (P/S) ratio was 0.34+/-0.06 in the group with overweight parents and 0.31+/-0.09 in the control group".

However you try to reverse engineer the limited data from the results it's hardly 5% vs 15% PUFA, but these people have taken around 25 years of eating a slightly heart-healthier PUFA rich-er diet to gain an excess of 1.7kg of fat mass. My biases are willing to accept this as real.

Maybe it is, maybe not. I'm not exactly a bias free source of opinion.

Peter

BTW leptin is consistently lower in the pre-obese group carrying excess fat mass. My suspicion is that their fat cells "feel" empty, so are refusing to signal their true state of fullness. Once the adipocytes become full enough then leptin will increase to give a more accurate representation of the absolute fat mass. This will be associated with the onset  of the more expected insulin resistance of obesity.