In the 1930s Clive McCay, a biochemist working in Ithaca, New York, made an interesting observation: rats that were kept on a low calorie diet lived longer than rats that had unrestrained access to food. In the next years this seemingly counterintuitive observation was extended to virtually all animals, including worms, flies and other rodents. Importantly, restricting the total amount of calories seems not only to increase lifespan, but to improve overall health of the individual and to delay the onset of neurodegenerative diseases and other pathological conditions linked to aging1.
Although the original protocol followed by McCay consisted exclusively in reducing the amount of total calories in the diet while maintaining the levels of micronutrients to avoid malnutrition, an alternative protocol termed “intermittent fasting” was soon adopted with similar results. The protocol consists on cycles where animals eat every other day: they first have free access to food for 24 hours, and then are kept the next 24 hours on strict fasting. An interesting observation is that animals on this diet lose weight, despite the fact that the amount of food intake in the long term is similar to controls due to overeating on feeding days. Rats, like everything else on the Universe, have to obey to the first law of thermodynamics, which states that energy is neither created nor destroyed. If they eat the same amount of food and are not getting fatter, where is that energy going?
A group of researchers from the University of São Paulo has now shed some new light on the molecular mechanisms behind these observations2. They fed rats for three weeks either following a normal laboratory diet (unrestrained access to food) or an intermittent fasting protocol as described above. They observed that control rats ate only 20% more than animals on the diet, but their weight gain was more than 2-fold, and decided to further investigate this.
If animals on intermittent fasting eat about the same but weight less, the simplest explanation would be that they are assimilating fewer nutrients. And to a certain extent, that was the case: the total weight of the feces of these animals was similar, but it had a 15% higher content of cholesterol esters and triglycerides. However, it was difficult to link causally such a small difference with the effects observed.
In addition to excretion, animals can also dissipate energy in the form of heat, that being the main reason why people are so fond of gyms. A simple explanation was that maybe animals on intermittent fasting moved more and burnt more calories due to increased physical activity. Previous reports indicate that animals on restricted diets are often more active, which is believed to a conserved evolutionary trait: hunger makes you look more actively for food. But that was not the case in this model, where intermittent fasted animals showed similar or even lower rates of spontaneous activity than controls.
OK, so if animals were not doing more exercise, another possibility was that the diet induced a metabolic change in the cells to make them less efficient: when nutrients are converted by the cells to molecules they can use, some amount of energy is always released as heat, and if the conversion is inefficient that amount increases. A good tissue to test this hypothesis is muscle, since it is responsible for a high proportion of the energy consumed by the body. And where exactly in the muscle? Most of the energy obtained by the cells is produced in their mitochondria, the so-called “power plants of the cell”. If energy handling is altered in muscular cells, that is the place to look for changes, and in fact there are several works linking mitochondrial changes in response to diet. In this case, however, the total levels of skeletal muscle mitochondria from intermittent fasted animals were identical to that of the controls, and their energetic efficiency was also similar.
But having “normal” mitochondria does not mean that their workload is the same, just like the brand of a car doesn’t give us any information on how much is actually used. To study this, the researchers used special cages that measure how much oxygen is consumed by the animals and how much CO2 is released. Using them, they made some interesting observations. On fasting days, intermittent fasted rats consume the same amount of oxygen, but release less CO2, which indicates that they use fat preferentially over carbohydrates. Why? Because lipids are molecules more reduced than carbohydrates and require higher amounts of oxygen to be fully oxidized per molecule of CO2 released. This is consistent with another observation made on these animals: the levels of liver triglycerides are more than two-fold on feeding days compared to fasting days. On the other hand, on feeding days, animals on intermittent fasting consume more oxygen and release more CO2 (as expected, since they overeat), with no changes on the ratio of oxygen consumed/CO2 released, but with increased body temperature. What does this mean? That fat and carbohydrate are used in the same proportion as controls, but part of the energy obtained is being released as heat.
Finally, the overeating pattern was studied, which was done by measuring the expression of neurotransmitters in the hypothalamus, which is where appetite is controlled by the organism. There are two types of neurons involved in appetite control: orexigenic, which when are active promote hunger and food intake, and anorexigenic, which induce satiety, and each kind express specific neurotransmitters. As expected, animals on intermittent fasting had higher levels of orexigenic molecules during fasting, indicating that they were hungry. But surprisingly, these molecules were also increased on feeding days, meaning that rats feel hunger even after gorging.
The picture that emerges is that animals on intermittent fasting manage to keep slim by eating a bit less, assimilating worse the nutrients in the food, releasing more heat on feeding days, using fat over carbohydrates on fasting days, and being always hungry. It is tempting to try to extrapolate these observations to humans: is it a good idea to fast every other day to lose weight? Results of basic science must always be taken with caution, since their goal is to try to understand molecular mechanisms, rather than discover miraculous treatments, and animal models are just that: models. But if you ask me, it seems like this work supports an observation that is as old as any diet: the best way to lose weight is to be hungry.
- Amigo I. & Kowaltowski A.J. (2014). Dietary restriction in cerebral bioenergetics and redox state., Redox biology, PMID: http://www.ncbi.nlm.nih.gov/pubmed/24563846 ↩
- Chausse B., Solon C., Caldeira da Silva C.C., Masselli Dos Reis I.G., Manchado-Gobatto F.B., Gobatto C.A., Velloso L.A. & Kowaltowski A.J. (2014). Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating., Endocrinology, PMID: http://www.ncbi.nlm.nih.gov/pubmed/24797627 ↩