Getting enthused about scientific theories might be a niche hobby, but this one is something special. The Fructose Survival Hypothesis is a unifying theory. Not the unifying theory- this one is diet/evolution specific.
In scientific fields, there are often a few mutually exclusive but otherwise apparently accurate theories. Physics is notorious for this, and still awaiting the one true theory that will unite the various incompatible fields.
Biology in general is less divided, but the subsection devoted to diet and nutrition is an exception. There are somewhat more fad diets than theories about nutrition, but probably not all that many more. Keto. Low Carb. Paleo.
What’s really neat about the Fructose Survival Hypothesis is that it ties together apparently mutually exclusive ideas about diet.
The paper that I will be paraphrasing by section is The fructose survival hypothesis for obesity was published earlier this year by The Royal Society (yes- that Royal Society- the one that published Darwin.) And- even better- it is not behind a paywall. Read the whole thing at the National Library of Medicine.
Abstract, paraphrased: The fructose survival hypothesis suggests that obesity might be caused by improper activation of a survival switch. That survival switch is supposed to be activated before a crisis (like, say, a famine). The survival switch, when activated will make people hungry, thirsty, more inclined to go look for food, and gain weight. It will also cause insulin resistance (diabetes), systemic inflammation and high blood pressure. This response is triggered by eating fructose, or by something that causes the body to make fructose. The response is supposed to be small and short- term, but the combination of some evolutionary changes and a diet with lots of foods that contain (or cause the body to make fructose) causes the switch to be activated much more often, to a much greater degree.
The authors propose that too much fructose explains a number of conditions we see in increasing amounts today: obesity, “diabetes, hypertension, non-alcoholic fatty liver disease, cancer’s associated with obesity, vascular and Alzheimer’s dementia, and even aging.” Additionally, the hypothesis unites current hypothesis on obesity. Reducing the activation of this survival switch might benefit health and lifespan.
Introduction, again, paraphrased: Scientists often don’t consider how nature and evolution have found solutions to problems, but looking at things that way can provide new insights. Evolution might also cause disease. Adaptations that are beneficial for a world with scarce resources might increase the risk for obesity and diabetes in a world with plentiful resources.
This study suggests that the survival switch is controlled by fructose. While glucose (a simpler form of sugar) provides immediate fuel, fructose seems to aid in the storage of fuel. This is because glucose and fructose influence the amount of energy available to cells differently.
This paper will talk about sources of fructose and will suggest two events that converted what should have been a helpful survival switch into something causing disease. The first event was gaining “thrifty genes” (genetics adapted for food scarcity), and the second event was the large increase in foods containing or producing fructose. Those two events cause the survival switch to be active far more than it should be, which the authors propose is driving obesity and other unpleasant modern health issues.
Sources of Fructose, The Trigger of the Survival Switch, paraphrased: Fructose is the main energy source in fruit and honey, but in the western diet it’s mostly in table sugar and high fructose corn syrup. These are a huge amount of people’s overall energy intake.
In the body, fructose can be made from glucose when the blood sugar is high, as it is with diabetes, eating “high gycaemic carbs” (carbs quickly converted to glucose) or from a diet high in carbohydrates. This happens at a higher rate when the body is stressed by lack of food, water, or oxygen. Salty foods and alcohol also cause this, as do foods that are savory. These can trigger fructose to be created in the liver, which turns on the survival switch. Fructose can be made in other organs as well.
Most animals control their weight pretty well. They’ll gain it if given extra calories, lose it if given too little, but as soon as their food supply normalizes their weight will correct itself. Fructose prevents this. It basically reduces the energy available to cells and also doesn’t let animals use the energy stored in their fat. Because of this, they have to eat more in order to have more energy available. While they do get the energy levels back up, they gain a lot of weight doing so.
Most studies on fructose produced by the body have been on lab animals, but there is evidence that feeding young, lean adults a high glycaemic (full of carbs that turn into sugar quickly) soft drink will greatly increase fructose production. The authors expect that fructose production will be higher in people with diets: high in salt, high in sugar, or with lots of high glycaemic carbs.
A Description of the ‘Survival Switch’ Induced by Fructose Metabolism, heavily paraphrased, as this section gets rather technical in places:
Giving a subject fructose can: replicate metabolic syndrome, cause weight gain, increase fat storage around the organs (“hidden fat”), cause insulin resistance, increased trigycerides, reduce “good” cholesterol, raise blood pressure, cause fatty liver, reduce levels of an important protein- Albumin, increases the amount of uric acid in the blood, and causes markers of systemic inflammation. This suggests that ‘metabolic syndrome’ is misnamed and would be more accurately called ‘fat-storage-syndrome’. All of these features are part of a survival response.
a) Search for food and water
Fructose causes changes in behavior that aid the search for food and water. These changes include: stimulating hunger and bingeing, stimulating thirst, impairing the ability to feel full, increasing exploratory behavior, impulsivity and movement. Studies suggest that some of these effects are caused by inhibiting the insulin-sensitive parts of the brain involved in self-control, memory and decision making.
b) Increase fat and glycogen stores
In addition to causing excess calorie intake, fructose changes the intestines so that they absorb food more effectively. It also causes the formation of fat and reduces the removal of fat.
c) Energy conservation
Even though the foraging behaviors require expending energy, this doesn’t result in lower fat gain because the resting metabolism falls to compensate. Fructose reduces the ability of insulin to signal to brain regions involved in self-control, decision making and recent memory. Because of this, foraging behavior is stimulated while energy is conserved.
d) Preservation of key body functions
Animals in risky conditions need to have well functioning circulatory and excretory systems. Fructose causes an increase in blood pressure and increases the activity of the kidneys. It also stimulates the production of a hormone that tells the body to reabsorb water (vasopressin) and causes the kidney and gut to absorb sodium.
e) Activation of the Immune System
Fructose increases the amount of uric acid, which activates inflammatory pathways (inflammation is the result of an active immune system). Immune system activation protects against infections.
f) Entering low power mode
Fructose metabolism changes the behavior of the mitochondria, placing the body in low power mode and reducing oxygen needs. This is initially helpful in areas with inflammation and reduced blood flow, but is a problem long-term. Reducing mitochondrial function is a characteristic of diabetic kidney disease, which is caused by glucose being turned into fructose in the kidney. It seems like blocking glucose from being taken into the tissues (and thus being converted to fructose) might be a useful treatment. The effect fructose has on mitochondria provides an explanation for why cancer cells prefer fructose to grow in, and why cancer cell growth is increased by both fructose and uric acid.
Role of Fructose Metabolism in the Obesity and Metabolic Syndrome Epidemics, paraphrased:
Obesity and Diabetes increased in the early 20th century. One likely cause is the dramatic increase in the amount of sugar people consume. Soft drinks and other liquids containing fructose are especially effective at activating the fructose survival mechanism. Speed of consumption appears related to the activation of the pathway, and the authors found that slowing down the intake of juice containing fructose reduced the activation of the pathway. Sugary beverage consumption correlates with the risk for obesity and metabolic syndrome. Similarly, the global increase in obesity and diabetes correlates with the increase in sugar intake. Also, people consuming more processed foods with lots of sugar and salt, as well as alcohol and high gycaemic carbs increases the amount of fructose.
There is evidence that humans are more sensitive to fructose. Mice and rats are generally fairly resistance unless large doses are given. In humans, there are two mutations that seem to increase the risk for fructose caused metabolic syndrome. The first is the mutation in vitamin C (humans can no longer make vitamin c). The second mutation was the uricase mutation (we can no longer make the enzyme that breaks down uric acid). This mutation was probably helpful during some points of human history, when it would have protected against starvation.
How does Fructose Cause Weight Gain, paraphrased:
Fructose increases food intake and lowers metabolism. Both of these should play a role in fat increase. Research with animals demonstrated that the weight gain is mostly caused by the increase in food intake.
The authors performed further studies to figure out what causes the increase in food intake. The sweet taste of fructose seems to help, but even mice without taste preferred fructose to plain water. Mice without the enzymes to metabolize fructose did not prefer it. The preference for fructose doesn’t seem to be causing the increase in food intake. Instead, the loss of the ability to feel full (leptin resistance) appears to cause the weight gain.
Animals getting read to hibernate show similar features to the survival switch, but right before they hibernate they reduce food intake. This might be because their metabolism is slowing, or it could be that they reach a weight that triggers a change in food intake. This mechanism does occur in humans, but can be overrun- possibly by continued exposure to large amounts of fructose.
a) Role of fat
Inability to feel full seems to be caused by fructose, while other foods (such as high fat diets) do not cause this. The inability to feel full (leptin resistance) causes a preference for high fat foods. The typical western diet likely includes enough sugar, salt, high gycaemic carbs and alcohol to induce some leptin resistance in most people. Testing the equivalent diet in mice resulted in aging changes for normal mice, but those that couldn’t metabolize fructose stayed healthy. This explains why the Inuit were able to stay lean on a high fat, high protein diet, and also why ‘low carb’ diets don’t cause weight gain even if they have high fat content. Lard (animal fat) doesn’t cause weight gain in mice unless they’ve been made unable to feel full by fructose.
b) Role of glucose
Most of the fructose we eat also comes with glucose. Glucose can increase the absorption of fructose. There is some evidence that glucose alone can cause obesity and metabolic syndrome. High glycaemic carbs (those quickly turned into glucose) cause obesity and metabolic syndrome by causing the body to produce fructose. When insulin resistance is induced by fructose, there are high insulin levels even when fasting, which prevent fat metabolism. The hypothesis that glucose causes insulin resistance is supported, but with fructose as a middle step.
c) Role of protein
Protein is important to maintaining lean body mass. There’s some evidence that low protein diets might cause increased energy intake. But, because most low protein diets are also high in carbohydrates, it’s difficult to tell which is more important.
Some proteins may cause increased risk for illness. Umami generates uric acid, leptin resistance, obesity and metabolic syndrome similar to fructose. Blocking the uric acid production did prevent MSG (monosodium glutamate) causing obesity. While uric acid can directly activate the siwtch, it can also stimulate fructose production. Fructose is produced by glucose, which is why high protein diets without carbohydrates (glucose sources) do not cause obesity.
Fructose and Metabolic Syndrome: An Effect Independent of Excessive Calories, paraphrased:
Even when rats with the fructose survival mechanism activated were kept on a strict diet (preventing weight gain), they still developed the other effects of fructose. The rats developed fatty liver, insulin resistance and high blood pressure. This suggests that metabolic syndrome can occur even in thin individuals, especially if excess uric acid is present in the blood.
The Unexpected Role of Salt, Dehydration and Vasopressin in Obesity, paraphrased:
Water is very important, so it makes sense that fructose increases water retention. Vasporessin does more than just cause water to be reabsorbed in the kidneys. It seems to drive most of the features of the survival switch.
Fat is used as a source of water by marine and desert mammals, as well as animals that are hibernating. Salt intake can cause a dehydration-like state without actual dehydration, and this can cause the production of fructose (and thus activation of the survival switch). Drinking water, which reduces vasopressin levels, can partially stop or reverse the features of metabolic syndrome.
The Short and Long-Term Health Consequences of the Survival Switch, paraphrased:
Having the survival switch activated continuously has metabolic effects that may involve many of the common diseases occurring in western society. “This not only includes classic diseases associated with obesity such as diabetes, NAFLD and gout, but also hypertension, coronary artery disease, certain cancers, behavioural disorders and dementia.”
For example, adding fructose to the diet can cause Alzheimer’s features in laboratory rats, and fructose is increased in the brains of people with early Alzheimer’s.
One important discovery is that the fructose pathway is involved in the early disease. Over time, there is damage that results in the persistence of the disease. This suggests the best time for treatment is early, before conditions become irreversible. However, since much of the disease is caused by damaged mitochondria, trying to restore mitochondria is a good approach (Low fructose and low salt diets, also exercise, would be a good place to start).
Wow. There’s a little more -limits, predictions, a summary- but that’s the paper. A new biological mechanism (fructose survival hypothesis) potentially explaining a bunch of the diseases of modern life and suggesting a relatively simple means to begin treating/preventing them.
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