We've been having an interesting discussion in the comments about a recently published paper by Dr. Stephen C. Benoit and colleagues (free full text). They showed that a butter-rich diet causes weight gain and insulin resistance in rats, compared to a low-fat diet or a diet based on olive oil. They published a thorough description of the diets' compositions, which is very much appreciated!

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. 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. I believe we're looking at a well-coordinated system designed by evolution to ensure that the glucose content of the blood remains stable.

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