Forewarned: Researchers map a timeline of damage caused by obesity

29 Sep 2017 --- A new experiment has set out a timeline of obesity’s negative effects. The study in mice showed that the neuronal damage associated with an obesogenic diet starts well before the individual begins to gain weight, but can be reversed early in the process. However, if the inadequate diet persists, injury to the neuron becomes irreversible.

Over the past decade, when investigating the factors associated with the growing epidemic of obesity in the world, scientists have identified two events that greatly contribute to weight gain. The first is the alteration in the profile of bacteria that make up the intestinal flora, while the second is the death of a group of neurons found in a region of the brain called the hypothalamus. Known as POMC neurons, these cells function as nutrient sensors that tell the body that it is time to stop eating and that there is enough energy to expend.

“We began to ask ourselves: what comes first? The change in the patient's eating patterns caused by an error in the system of the brain that controls hunger, or a change in the intestinal microbiome?” says Licio Augusto Velloso, coordinator of the Obesity and Comorbidities Research Center at the University of Campinas (UNICAMP) in Brazil, Sao Paulo state.

“Our most recent data suggest that the hypothalamus is damaged well before changes occur in the intestine,” Velloso adds.

“We began to detect hypothalamic alterations on the very first day of the obesogenic diet. But it took about two to three weeks for changes in the intestinal microbiota to appear. This is a relatively big time difference, considering that they are mice,” Velloso explains.

Damage to neurons
In previous studies, the group from UNICAMP had described how damage to the POMC neurons occurred. The molecules of saturated fat ingested are absorbed by the intestine, enter the bloodstream and reach the brain together with the other nutrients in the food.

In the central nervous system, defense cells known as microglia understand that the excess fat is a threat to the neurons and begin to produce inflammatory molecules as if they were combating a pathogen.

“Initially, the inflammation undermines the proper functioning of the hypothalamic neurons. If this goes on for too long, the cells end up dying,” Velloso says. “This is probably the reason why individuals who have been obese for a long time have trouble losing weight and keeping weight off after various treatments. These individuals are simply no longer able to achieve balance in the flow of energy in the body.”

Velloso adds that if an individual has a meal rich in saturated fats, but then spends several days ingesting a high-fiber diet supplemented by vegetables, the inflammation in the hypothalamus diminishes and the neurons recover.

“What cannot happen is that the obesogenic diet becomes more frequent because it will lead to a gradual increase in the inflammatory process,” Velloso warns.

An unbalanced diet changes a series of metabolic parameters, promoting the development of diabetes and hypertension. In this context, says Velloso, the change in intestinal microbiota emerges, which in turn contributes to aggravating obesity as well as the diseases associated with it.

According to Velloso, studies by other groups have shown that a diet rich in simple carbohydrates – such as those in sugar and white flour – can also increase lipid levels in the blood and indirectly promote inflammation in the hypothalamus.

“When comparing the two types of diets, however, the researchers concluded that the results are worse when there is excessive consumption of saturated fat,” Velloso says.

The leading sources of saturated fat in the human diet are foods of animal origin such as fatty meats, butter and dairy products. But that nutrient is also found in oil and by-products of coconut and in palm oil as well as in various processed foods such as cookies, ice cream, cakes and pies.

Neurogenesis may be future solution
According to Velloso, recent studies suggest that it is possible to promote neurogenesis in the hypothalamus – in other words, to stimulate the emergence of new POMC neurons in an attempt to fight obesity. But this has only been tested in experiments with laboratory rodents. Much more research is needed to understand how the process of cell differentiation can be controlled.

“We are currently at the stage where we understand how the neural precursor cells, a type of stem cell found in the brain, function,” Velloso says. “We need to determine which factors have to be activated to trigger the process of neurogenesis. It is a first step, but may end up being a therapeutic solution to obesity in the future.”