They went on to show that infusing palmitic acid (a 16-carbon saturated fat) directly into the brain of rats also caused insulin resistance relative to oleic acid (an 18-carbon monounsaturated fat, like in olive oil). Here's a representation of palmitic acid. The COOH end is the acid end, and the squiggly line is the fatty end. Thus it's called a "fatty acid", various forms of which are the fat currency of the body.
One of the most interesting things about this study is the butter group that the investigators fed the same number of calories as the low-fat group (this is called pair-feeding). This group did not become overweight, and did not experience elevated fasting insulin and blood glucose relative to the low-fat group*. This shows clearly that the adverse effects of the butter diet were primarily due to the fact that rodents overeat when fed a high-fat diet.
Unfortunately, the paper doesn't provide longitudinal food intake data so we have no idea how many calories the rats in each group ate, beyond knowing that the low-fat group and the pair-fed butter group ate the same amount. We have no assurance that rats in the butter group and olive oil group ate the same number of calories over time. Rats eat less of foods they find bitter. This probably accounts, at least in part, for the beneficial effects of things like blueberry extracts on rodent models of disease. Olive oil may taste bitter to a rat, particularly when it's 20% of the diet by weight. Butter is tasty to calves, humans and rats alike.
Now we arrive at the speculative part of the post. I've been pondering a tough question for months. Palmitic acid has aroused universal ire for its supposed effects on lipid metabolism and insulin sensitivity**. But that leaves us with a puzzling paradox: palmitic acid is precisely the fatty acid that the liver produces when we eat carbohydrate. Our bodies contain the enzymes necessary to desaturate palmitic acid, making it monounsaturated. Why don't we use them? Why does the liver choose to secrete palmitic acid into the bloodstream unmodified? A fundamental metabolic process like this does not evolve by accident.
Here's the hypothesis. I believe that palmitic acid in the bloodstream does promote insulin resistance in rodents and probably humans as well. But there's a twist: it's probably not pathological at all; it's simply serving as a reversible signal to conserve blood glucose. This is similar to the hormone glucagon, which increases glucose production by the liver in response to falling blood glucose. Let's imagine an average person's eating habits throughout the day. Breakfast is at 8:00 am, lunch is at noon, and dinner is at 7:00 pm. The meals are about 45% carbohydrate, 40% fat and 15% protein. Let's imagine the fat consumed is animal fat, which contains some palmitic acid (25-30% of fatty acids).
The carbohydrate will be absorbed, partially turned into palmitic acid in the liver, and exported as VLDL particles. The amount of palmitic acid produced depends on the intake of starch and fructose, and will be relatively small except in the case of high carbohydrate or fructose consumption. Dietary fat will be absorbed in the intestine and sent out directly as chylomicrons (another lipoprotein particle). This is delayed relative to glucose absorption, such that the palmitic acid from both sources will enter the bloodstream at a similar time (peaks roughly 4 hours post-meal). Here is a hypothetical graph of blood glucose and blood palmitic acid at different points throughout this person's day (based on data such as these):
Notice a pattern? The concentrations of blood glucose and palmitic acid in the blood are approximately opposite one another. The brain responds to palmitic acid by temporarily decreasing the insulin sensitivity of other tissues, because it uses palmitic acid as a signal to begin conserving blood glucose while insulin is still elevated. Glucagon increases glucose secretion by the liver, and palmitic acid makes sure the glucose isn't removed from the bloodstream too quickly. I believe we're looking at a well-coordinated system designed by evolution to ensure that the glucose content of the blood remains stable after a meal. There are two other scenarios in which this type of system would be advantageous. Let's imagine Nanook the Inuit has just killed a caribou in September. He eats some of the meat and organs with a generous slab of backfat. Large male caribou in the fall can carry a deposit of subcutaneous fat on their back that weighs up to 50 pounds. This fat is about 50% saturated, and roughly 25% palmitic acid. Here's a quote from the book My Life With the Eskimo, published by the anthropologist Vilhjalmur Stefansson in 1913:
The largest slab of back fat which I have seen taken from a Caribou on the Arctic coast was from a bull killed near Langton Bay early in September, the fat weighing 39 pounds. A large bull killed by Mr. Stefansson on Dease River in October had back fat 72 mm. in thickness (2 7/8 inches). Comparing the thickness of this with the Langton Bay specimen, the back fat of the Dease River bull must have weighed at least 50 pounds.As the food is digested, Nanook's insulin rises to allow amino acids from the protein to be absorbed into his tissues from his bloodstream. But wait, insulin also tells tissues to absorb glucose, and the meal contained virtually no carbohydrate. Nanook is in danger of hypoglycemia. Fortunately, his brain detects the palmitic acid from the meal and signals his tissues to become resistant to the glucose-transporting effect of insulin. At the same time, glucagon signals the liver to release glucose into the bloodstream. His blood glucose remains stable.
The next week, the herd of caribou has moved on and there's no prey in Nanook's territory. He has to live on his own body fat for two days while he hunts. Fortunately, human body fat is about 20% palmitic acid. As fat is released into his bloodstream, the brain detects the palmitic acid and reduces peripheral insulin sensitivity. This helps Nanook's body conserve glucose and use his own body fat as fuel instead.
Over a wide range of fat, carbohydrate and calorie intakes, this system works to maintain stable blood glucose. These three scenarios all illustrate why palmitic acid would be helpful by causing temporary insulin resistance in situations where blood glucose needs to be conserved.
Back to the paper. The authors also showed that force-feeding rats large amounts of palmitic acid and calories (much more than would be present in animal fat) causes changes associated with insulin resistance in the brain. What I believe they have done is overstimulate this natural pathway for regulating insulin sensitivity by feeding unnatural amounts of palmitic acid.
Rats fed the butter diet at the same number of calories as the low-fat group did not exhibit metabolic dysfunction, showing that a reasonable amount of palmitic acid is compatible with metabolic health in this species. I believe this is even more true in humans, given our evolutionary history with animal fat and carbohydrate, both of which contribute palmitic acid to the circulation. Our deep-seated fear of saturated fat may have caused us to mistake a natural aspect of mammalian metabolism for a pathological process.
* The pair-fed butter group did show a lowered sensitivity to insulin, but given its normal weight, normal fasting insulin, and normal blood sugar, it really cannot be said to exhibit metabolic dysfunction in my opinion. Human "metabolic syndrome" involves overweight and elevated fasting insulin, which these rats did not have. Furthermore, the investigators did not show that the insulin sensitivity of the pair-fed butter group was different than a pair-fed olive oil group (they didn't make that comparison), so the finding doesn't implicate saturated fat specifically. Insulin sensitivity is determined in part by carbohydrate intake. This is normal. The more carbohydrate the body has to dispose of, the better it gets at handling it. On a high-fat diet, you don't need much insulin sensitivity to keep blood glucose in the normal range, because you aren't ingesting much glucose. On the other hand, in high-fat (low carbohydrate) diet trials on insulin-resistant people, insulin sensitivity often improves, however this is not the case in healthy insulin-sensitive people.
** The idea of palmitic acid's effect on insulin sensitivity is based largely on animal models and cell culture data. A long-term (rather than temporary and reversible) effect of palmitic acid on insulin sensitivity has never been convincingly demonstrated in humans, to my knowledge. After reviewing the literature, I've also concluded that a long-term, biologically significant effect of saturated fats in general on insulin sensitivity has not been convincingly demonstrated. I'll save that for another post.
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