Food, Nature, and Metabolic Disease
In the last post, we discussed how the depletion of glutathione and antioxidant-supporting vitamins and minerals can lead to oxidative stress in the hypothalamus. This stress triggers inflammation to repair neuronal damage, inhibiting leptin signaling and increasing the brain’s preferred adiposity level for the body. In other words, oxidative stress leads to chronic overeating, which then contributes to obesity. In this post, we’ll explore oxidative stress in the context of other metabolic diseases and how it serves as a useful adaptive mechanism in nature for humans to survive during times of food scarcity.
Obesity and other metabolic diseases are closely related. Obesity is often mistakenly thought to cause issues like heart disease, diabetes, and certain cancers. In reality, while obesity is closely tied to these issues, it is not the direct cause. The root cause of all these problems is metabolic dysfunction (insulin resistance), which is driven by oxidative stress. Ben Bikman’s book Why We Get Sick delves into how insulin resistance contributes to these diseases, and I highly recommend reading it. Bikman advocates for a ketogenic diet to avoid insulin resistance, assuming that it is caused by high insulin secretion. This post will present an alternative idea that may conflict with that hypothesis. Nonetheless, it’s an excellent resource for understanding how metabolic dysfunction contributes to a plethora of chronic diseases.
While metabolic dysfunction is problematic in modern society, could it have been an important adaptive mechanism in past human history? A book that explores these ideas is Nature Wants Us to Be Fat by Dr. Richard Johnson. The primary focus is on fructose, with examples of how other animals use fructose in nature to store fat for hibernation, long-distance travel, or because their metabolism is extremely fast.
Fructose is a sugar found in nature, present in fruit and honey, along with glucose. Fructose and glucose are also found in refined sweeteners like table sugar and high fructose corn syrup. The book also explores other secondary mechanisms, such as dehydration, that cause the internal production of fructose. Johnson’s idea is that fructose consumption activates a “survival switch” that causes humans and other animals to slow down their metabolism and promote fat storage. Experiments on rats have demonstrated that fructose metabolism generates uric acid as a byproduct, which then causes oxidative stress on cellular mitochondria, leading them to use less energy, resulting in more energy being stored as fat. Furthermore, leptin resistance was observed in the rats, contributing to an increase in appetite. I explored leptin resistance in more detail in my previous post.
The first time I read this book, my main takeaway was that carbohydrates, especially those rich in fructose (though glucose is also converted to fructose to some degree), should be eaten sparingly to avoid a metabolic downward spiral, as ripe fruit is often available only seasonally in nature. But as I thought more about it, I asked myself a very important question: what if it’s not fructose that’s the issue, but oxidative stress in general?
The problem with experiments on rats is that they are fed high concentrations of pure fructose to control for a single variable, rather than considering the context of their entire dietary pattern. If we look through the lens of oxidative stress, we realize that there are other factors, in addition to increased fructose consumption, that contribute to higher oxidative stress.
In nature, how does the food environment change as winter approaches?
Fruit reaches peak ripeness.
Animals migrate to warmer areas or go into hibernation.
Nuts and seeds are available for harvest.
A combination of increased fructose intake from ripe fruit, increased polyunsaturated fat intake from nuts and seeds (lipid peroxidation), and lower protein and saturated fat availability from migrating or hibernating animals will lead to higher oxidative stress in humans. Recall from the last post the hypothesis that oxidative stress is the root of leptin resistance, which makes the hunger neurons in the hypothalamus more active. This adaptation would allow humans to have a higher appetite due to hypothalamic stress, combined with a lower metabolism from mitochondrial stress, when they need it most to store a few extra pounds of fat for the winter, which can mean the difference between life and death.
Johnson’s metaphor of a “survival switch” is also misleading because it suggests a simple dichotomy between a tendency to stay lean and metabolically healthy versus a tendency to gain weight and be disease-prone. He writes in the book that it can be triggered and stifled to different degrees, so he recognizes how it can be misinterpreted. In reality, the switch is likely to be a continuum of how much oxidative stress accumulates. An evolutionarily appropriate amount of oxidative stress might lead to a few pounds of additional body fat, while a large amount can lead to much greater fat accumulation and other complications. It’s a system that needs to be flexible because it’s present in so many animals, and some animals need to trigger this stress to a greater degree than others. Additionally, for humans specifically, varying degrees of stress may have been more appropriate for different climates. Johnson cites oxidative stress repeatedly in his book, and also research suggesting that antioxidant therapy has been shown to dampen it, but still presents fructose as the main villain.
At first, the book seems to confirm the repeated idea in the low-carb community that insulin resistance and resulting diseases are caused by high carbohydrate intake. But what if oxidative stress is the root of insulin resistance? Reactive oxygen species (ROS) provide an important signaling role in muscle and liver cells, indicating when the cell should stop metabolizing glucose and fatty acids. These cells temporarily become insulin resistant and delegate excess energy to adipose tissue (fat cells). If the cells continued metabolizing energy, they would keep generating ROS from normal metabolism and essentially destroy themselves. They need time to clear ROS and repair.
What happens when fat cells themselves accumulate ROS and become insulin resistant? It becomes harder for blood glucose to be brought down appropriately because insulin is not able to help transport glucose into cells as effectively. The brain wants to keep blood sugar stable at all costs, so it signals the pancreas to secrete more insulin, which gets the job done. But the result is hyperinsulinemia, which is the first step in diabetes progression. As oxidative stress continues to become more severe, cells become more insulin resistant, and eventually, the pancreas simply cannot secrete enough insulin to keep blood glucose at appropriate levels. That’s when hyperglycemia is observed, and a blood test will reveal elevated fasting blood glucose. Unfortunately, despite fasting blood glucose being the universal test for metabolic health, it’s a lagging indicator because chronic insulin resistance has already been progressing for some time. A fasting insulin test is a much earlier indicator of a problem. Finally, fasting blood glucose reaches a point at which a patient is diagnosed as fully diabetic, and the pancreas can no longer secrete enough insulin to keep blood glucose at any reasonable level; the patient must inject exogenous insulin to stay alive.
That’s why conventionally, insulin resistance has been thought to be a problem of eating too much. If that’s the case, why does smoking also cause diabetes? It’s true that eating less can improve insulin sensitivity because when less energy is metabolized by fat cells, fewer ROS are created, leading to less oxidative stress and therefore better insulin sensitivity. But eating less with willpower alone doesn’t work because consuming a diet full of stressful foods keeps appetite high due to oxidative stress persisting in the hypothalamus. Different dietary patterns lead to different amounts of hypothalamic oxidative stress, causing people following different diets to have brains that prefer different adiposity levels. Instead, choosing proper foods is a much better way to limit oxidative stress and consequently lower appetite. That’s why this controlled trial showed a much larger calorie intake from those consuming ultra-processed food versus minimally processed food, despite matching presented calories, sugar, fat, fiber, and macronutrients for both diets. The previous post details the mechanisms behind these concepts.
Furthermore, as Johnson mentions, oxidative stress on cellular mitochondria slows down metabolism, and a higher amount of consumed energy is confined to fat storage. Remember, ROS signaling dictates when a cell stops energy intake and delegates the excess energy to adipose tissue. That means more calories from a high-stress diet will be stored as fat than those from a low-stress diet, leading to more fat storage on a high-stress diet even if calorie intakes between the diets are equal. Additionally, even if food intake on a high-stress diet is low enough to maintain some level of leanness, metabolic disease will still be present according to Johnson’s research.
Unfortunately, antioxidants are more frequently heard as a pop culture health buzzword than actual science, but there’s substantial scientific evidence highlighting the importance of the antioxidant defense system and how a deficiency in that system leads to the metabolic problems we see today. Luckily, instead of listening to astrology-obsessed almond moms telling you to buy $30 acai bowls and chug green smoothies, you can refer to my simple food guide to learn how to bolster your antioxidant defense.