Intermittent fasting deregulates the cerebral mechanism for controlling hunger

Karina Toledo/Agência FAPESP/DICYT Diets that alternate between cycles of prolonged fasting and regular eating are capable of preventing excessive weight gain but may also cause undesirable metabolic changes, such as deregulating the brain mechanisms that control appetite.

These conclusions are from a study that was conducted on rats at the Chemistry Institute of the University of São Paulo (USP) and recently published in an article in the journal Endocrinology.

The study was conducted during the doctoral research of Bruno Chausse under the scope of the thematic project “Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism,” coordinated by Professor Alicia Kowaltowski. This study is also associated with the work of the Center for Research on Redox Processes in Biomedicine (Redoxoma), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.

“Previous studies have shown that animals subjected to intermittent diets ended up eating nearly the same amount of food as rats in the control group because they compensated for times of deprivation when food was available. Despite this, they gained less weight. What we would like to understand, from the metabolic standpoint, is how this occurs,” explained Kowaltowski.

During the three-week experiment, 8-week-old rats – considered young adults – were divided into two large groups. The animals that were subjected to the intermittent diet alternated between 24-hour periods of fasting and 24-hour periods of unrestricted feeding. Rats in the control group received as much food as they wanted for the entire period and, after three weeks, demonstrated a nearly 11% increase in weight.

“Even with access to food for half the amount of time, animals on the intermittent diet ingested the equivalent of 80% of the amount consumed by the control group, which indicates the occurrence of hyperphagia during the time that food was available,” said Chausse.

In addition to monitoring the quantity of food ingested, the researchers also observed water consumption and the production of urine and feces. “One of the possibilities that we needed to exclude was that excess food was not being absorbed and ended up being eliminated in the feces. But there was no difference in the volume of waste, which reinforced the idea that this was indeed a metabolic change,” said Chausse.

The next hypothesis that the group investigated was whether the lower weight gain was associated with a type of short circuit in the mitochondria, which would make them less efficient at converting energy from food into body mass.

But comparing the mitochondrial function of important tissues, such as musculoskeletal tissue, the group observed no significant difference between the control group and the group on the intermittent diet in the production of the adenosine triphosphate (ATP) molecule, which is an energy store.

The next step was to compare overall metabolic activity. The rats were placed in chambers that allowed the measurement of their oxygen consumption and carbon dioxide production through an assessment known as indirect calorimetry.

“We saw that when the animals on the intermittent diet were fed, there was an increase in their metabolic rate, and they began to use more energy. On fasting days, however, the organism consumed a lot of lipids; in other words, the rats burned more fat. We believe that the association between these two factors explains the lower weight gain,” said Chausse.

Alterations in the hypothalamus

In partnership with Licio Velloso, a professor at the University of Campinas (Unicamp) and coordinator of the Multidisciplinary Research Center on Obesity and Associated Diseases (CMPO), the USP group investigated possible alterations in the hypothalamus that could be triggered by the intermittent diet.

The researchers observed that during fasting, there was a nearly 30% reduction in a neurotransmitter called thyrotropin-releasing hormone (TRH), which is associated with the release of hormones from the thyroid. This reduction is one possible explanation for the variation in the metabolic rate but still requires further study.

“But overall, what got our attention was the significant increase in the neurotransmitters AGRP [agouti-related protein] and NPY [neuropeptide Y], which are responsible for stimulating the appetite,” explained Chausse.

The researcher added that the levels of these neurotransmitters normally drop after meals; however, in animals on the intermittent diet, the levels remained twice as high as those in the control group. This finding suggests that the dieting rats continued to be hungry, even when their stomachs were full.

“We suspect that they just did not eat the same amount (it would be closer to 80%) as the control group due to a lack of space in the gastrointestinal tract,” said Chausse.

Levels of the hormone ghrelin (which stimulates hunger and is produced as the stomach empties) and leptin (an appetite suppressant) were also evaluated.

“Although we observed no difference in the production of ghrelin, we suspect that the brain of the animals on the intermittent diet became more permeable to the entry of this molecule. The brain was also sensitive to the action of leptin, but the production of this satiety hormone was reduced by half in the group on the intermittent diet,” said Chausse.

The researchers now plan to investigate whether appetite control changes can be reversed with a return to normal patterns of eating.

In a previous study conducted during the doctoral studies of Fernanda Cerqueira and published in the journal Free Radical Biology and Medicine, the group tested the long-term effects of the intermittent diet.

Nine months after the experiment, the animals continued to be thin but had become resistant to the action of insulin. According to the researchers, this negative effect could be associated with increased production of oxidizing substances such as oxygen free radicals, which damaged the insulin receptors in the cells.

Cerqueira’s study further showed that although the animals subjected to the intermittent diet were lighter, they had the same amount of body fat as animals in the control group, which indicates that the lower weight was due to a loss of lean body mass.

“We cannot directly translate the findings of these studies to humans because 24 hours of fasting for a rat is equivalent to several days of fasting for humans. But the results indicate that from the metabolic standpoint, this type of diet is different from the typical calorie-restricted one [when daily caloric intake is reduced by 20%]. One important finding that could be translated to humans is that not all weight-loss diets are completely healthy,” said Kowaltowski.