Is Oxidative Stress the Root Cause of Obesity?

Imagine an average 200 lb., sedentary, 5’10” man who decides on a straightforward weight loss strategy: follow the exact same dietary pattern as before, but cut all portions by 20%. How much weight will he lose in two years?

It’s a trick question because the answer is almost certainly zero pounds. If he’s able to sustain a 20% calorie deficit for two years, he will lose a significant amount of weight. However, sustaining such a deficit is difficult because the brain fights against changes in adiposity. Given that this hypothetical man is not changing the foods he eats, but only the portion sizes, his brain will compensate for the calorie loss by increasing feelings of hunger. So, unless this man has ironclad willpower indefinitely, he’s not likely to lose any weight long-term. What is the mechanism behind this, and how can one alter their brain’s preferred adiposity?

Unraveling the Paradox of Leptin Resistance in Obesity

Leptin, a hormone produced by adipose tissue, plays a vital role in regulating hunger by signaling satiety to the brain's hypothalamus. Normally, increased body fat raises leptin levels, signaling the body to eat less and use more energy. However, in many obese individuals, this system does not work properly, a condition known as leptin resistance. Despite high leptin levels, they continue to feel strong urges to eat, as their hypothalamus fails to respond to leptin’s hunger-suppressing signals.

Understanding leptin resistance is crucial for addressing obesity and exploring how diets affect our brain’s ability to regulate body weight. Research highlighted in Dr. Stephan Guyenet’s book "The Hungry Brain" discusses the complex interaction between diet, brain biochemistry, and leptin resistance. Specifically, in the hypothalamus, leptin usually deactivates hunger-promoting neurons (NPY/AgRP) and activates satiety-promoting neurons (POMC). High leptin levels also diminish the brain's reward responses to food, lessening the urge to eat. Nonetheless, in obese individuals, higher leptin levels do not enhance satiety, suggesting a malfunction in hypothalamic response to leptin, underlying the persistence of hunger.

The Old Hypothesis: Short-Term Overeating as the Culprit

No one knows exactly why leptin signaling is weaker in obese individuals, but Guyenet proposes one researcher's idea that the hypothalamus might develop a tolerance to excessive leptin signaling triggered by overeating in the short term. This would mean that an overeating individual would require more leptin, and thus more food, to feel just as satiated in the future as they do with less food in the present. According to this hypothesis, it might be beneficial for an individual to avoid eating highly palatable foods, which can lead to increased calorie consumption in the short term. Perhaps eating less palatable foods with more fiber and nutrients is a way to prevent overeating and therefore avoid leptin resistance.

The hypothesis is highly speculative, and Guyenet notes it as such. The idea that eating good-tasting food leads the brain to chronically overeat and store more fat doesn’t make much sense as a homeostatic adaptation. Moreover, where should the line be drawn regarding how good food is supposed to taste? Avoiding the most palatable foods might work, not because these foods are inherently enjoyable, but because they tend to be ultra-processed junk food. Instead, let's try to fill in the gaps and build a more compelling hypothesis. An interesting finding that Guyenet notes is that when studying obese mice, inflammation is observed in the brain, specifically in the hypothalamus. Even more intriguing is that the inflammation precedes actual obesity and is a primary driver of the observed leptin resistance. This is where Guyenet’s analysis ends and our new analysis begins as we try to answer a key question: what is driving hypothalamic inflammation?

A New Hypothesis: Oxidative Stress as the Culprit

It turns out that the hypothalamus is not only uniquely susceptible to inflammation but also uniquely susceptible to oxidative stress from obesogenic diets. I am proposing a new hypothesis: oxidative stress triggers inflammation in the hypothalamus, which impairs leptin signaling. This, in turn, increases hunger and leads to a preference for a higher equilibrium adiposity level.

Oxidation is an inevitable aspect of energy metabolism; occasionally, electrons from the electron transport chain escape and bind to oxygen molecules inhaled during respiration. Electrons naturally seek pairs, so an oxygen molecule that gains an extra electron becomes a superoxide radical. This highly reactive molecule can then damage the lipids, proteins, and DNA within cells. Fortunately, the body’s antioxidant defense system can keep these radicals and their reduced forms, collectively known as reactive oxygen species (ROS), under control, thereby maintaining proper redox balance. However, an excessive buildup of ROS (oxidative stress) can cause damage to cells. This damage triggers inflammatory pathways that impair insulin and leptin signaling. Such inflammation is an important mechanism to help cells repair ROS damage, while the impedance of insulin and leptin receptors allows cells to conserve energy, thus avoiding additional ROS buildup. This is beneficial for cellular repair but detrimental to satiety signaling in the brain because it reduces the effectiveness of leptin in inhibiting hunger-promoting NPY/AgRP neurons.

If true, this hypothesis would redefine obesity from a problem rooted in overeating to one of oxidative stress. Taxing the body’s antioxidant defense system, whether through dietary or other means, reduces the supply of its endogenous antioxidants: superoxide dismutase and glutathione.

Why Ultraprocessed Foods Are Obesogenic

Experts have speculated for years why ultraprocessed foods are far more obesogenic than whole foods. One prevailing theory is that they are “hyperpalatable” and therefore trigger overeating. While this is true in the short term, just as the brain resists weight loss by increasing hunger during a calorie deficit, it should also resist weight gain by decreasing hunger in a calorie surplus. This suggests that short-term calorie intake shouldn’t significantly affect the brain’s preferred adiposity level in the long run. However, viewing ultraprocessed foods through the lens of oxidative stress provides a clear explanation. Ultraprocessed foods:

  1. Typically have little protein. The amino acids glutamate, cysteine, and glycine, which come from eating high-quality proteins, are needed to synthesize glutathione, the body’s master antioxidant.

  2. Are filled with refined oils (seed oils) composed primarily of polyunsaturated fats, which are uniquely susceptible to lipid peroxidation both inside and outside the body due to their carbon-carbon double bonds. Fighting lipid peroxidation requires vitamin E, which is recycled by vitamin C, which in turn is recycled by glutathione. Low levels of vitamin E and vitamin C in the context of lipid peroxidation can lead to glutathione depletion, while also allowing further lipid peroxidation in a chain reaction from the highly reactive lipid peroxyl radicals. Moreover, even with abundant vitamin E, lipid peroxyl radicals are reduced to lipid peroxides, which still require glutathione for further reduction into hydroxy fatty acids. Thus, a high intake of seed oils can deplete glutathione even with sufficient vitamin E and vitamin C.

  3. Are bereft of micronutrients. Manganese, copper, and zinc are needed for superoxide dismutase, which reduces the superoxide radical into the more stable hydrogen peroxide (still an ROS, but less reactive). Iron and selenium, along with glutathione, are needed to reduce hydrogen peroxide into water. The B vitamins niacin and riboflavin assist in glutathione recycling during energy metabolism (NADPH synthesis through the pentose phosphate pathway during glycolysis).

  4. Contain numerous strange additives. Glutathione is used to expel xenobiotics from the body, so consuming these foreign substances will further deplete glutathione.

  5. Contain refined sugar. Unlike natural high-sugar foods, such as fruit and raw honey, which contain antioxidants and nutrients that support the body’s antioxidant defense, refined sugar offers no additional nutrients or antioxidant benefits to combat ROS byproducts from its metabolism.

Through a combination of high energy, few nutrients, seed oils, and additives, ultraprocessed foods are perfectly designed to deplete the activity of superoxide dismutase and glutathione in cells.

The Solution to Being Too Hungry

Here’s a concise review of the hypothesis:

In the context of hunger neurons specifically, oxidative stress in the hypothalamus triggers inflammation, which inhibits leptin receptor sensitivity. Consequently, higher amounts of leptin are required to inhibit the hunger-promoting NPY/AgRP neurons, leading to increased calorie intake.

Conversely, restoring proper antioxidant function should reduce oxidative stress in the hypothalamus, thereby lowering inflammation, increasing leptin sensitivity, and allowing the inhibition of NPY/AgRP neurons with lower calorie intake.

In other words, a healthy redox balance means appetite functions properly. A stressed redox balance results in an appetite that is higher than it should be. This implies that by restoring proper redox balance through food choices—rather than by restricting calories—we can normalize our neural biochemistry to regulate appetite. Beyond eliminating ultraprocessed foods from the diet, this guide contains some guidelines for making healthy food choices aimed at increasing leptin sensitivity by reducing oxidative stress.

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