Body tissue most vulnerable to metabolic changes caused by obesity

When the body is subjected to a hypercaloric diet, the physiological response is not homogeneous: some organs or tissues are more sensitive to this metabolic stress.

Under these conditions, the white adipose tissue of the visceral cavity is, among all organs and tissue types, the most vulnerable to obesity-related metabolic changes, according to a new study led by Professor Pablo M. Garcia-Roves , from the Faculty of Medicine and Health Sciences of the University of Barcelona (UB); the Bellvitge Biomedical Research Institute (IDIBELL), located in Hospitalet de Llobregat and which is part of the CERCA institution of the Generalitat de Catalunya; and the Center for Biomedical Research in the Physiopathology of Obesity and Nutrition Network (CIBEROBN), in Spain.

This vulnerability is manifested in the magnitude of the metabolic changes in obese animals and in the poor response of the aforementioned tissue when those same animals lose weight due to changes in lifestyle and return to being metabolically healthy. The study —based on an animal experimentation model— finds that, when physiological stress exceeds the response capacity of white adipose tissue, a point of no return is reached in which it loses its metabolic plasticity.

Members of the Faculty of Pharmacy and Food Sciences and the Institute of Biomedicine of the UB (IBUB), the IDIBAPS, the Rovira i Virgili University, the Ramon Llull University, the Center for Biomedical Research in Network of Diabetes and Associated Metabolic Diseases (CIBERDEM), the University of Santiago de Compostela, the universities of Cologne and Leipzig (Germany) and the Medical University of Innsbruck (Austria), among other institutions.

The extra kilos do not affect all tissues and organs equally. Some are more susceptible than others to the changes brought about by obesity. (Photo: Amazings/NCYT)

Obesity: metabolic dysfunctions and social stigma

Obesity, still stigmatized in our society, always generates important changes in physiology and metabolism. Many of the changes that we can describe in obese people could be considered mere physiological adaptations to the stress that excessive caloric intake implies. Now, to what extent can we make this excessive intake chronic? What is the limit to continue stressing our body?

“It is not an easy task to define these limits and this is one of the main challenges in studies on obesity and biology in general”, explain the researchers Pablo M. Garcia-Roves and Pau Gama-Pérez. “Exceeding these adaptive limits can be the trigger for all those comorbidities associated with obesity that are of great concern in terms of public health.”

One of the main functions of adipose tissue is to store fat and regulate excess calories. “If that fat were stored in other organs, the consequences would be much more counterproductive for health. The cells of the adipose tissue increase in size, multiply and communicate with each other to report the stress they have to face. Hypoxia and inflammation, for example, are essential signals for your cells to act in a coordinated manner, store excess fat and inform the brain that energy reserves are full”, explains Gama-Pérez.

Mitochondria at the point of no return

When these signals are not effective and the caloric excess becomes chronic, metabolic problems can appear and many cellular components stop working properly. Mitochondria —the cellular organelles responsible for generating metabolic energy— are a key element in understanding this physiological point of no return, the authors of the study point out.

“Many alterations in gene expression and protein synthesis in the adipose tissue of obese animals had some connection to the functioning of the mitochondria. In the study we found that several aspects of the morphology and structure of the inner membrane of the mitochondria were not optimal and this could have serious repercussions from the functional point of view”, emphasizes Garcia-Roves. “Specifically,” he continues, “one of the most significant discoveries is the very pronounced loss of the genetic material of this organelle, material known as mitochondrial DNA.”

A snowball effect on metabolic dysfunctions

The role of mitochondria in the metabolic dysfunctions that obesity produces in adipose tissue has already been described in the scientific literature. However, this study confirms for the first time that the pathophysiological trace caused by obesity is capable of lasting —and even accentuating over time— when the animals return to being healthy from the metabolic point of view or when other biological processes are altered. in the tissue they recover.

This physiological damage would be propagative in nature and could be defined as a snowball phenomenon triggered by the stress that chronic caloric excess entails for the adipose tissue. In this physiological dysfunction, peroxisomes, cellular organelles related to the metabolism of substrates and the elimination of reactive oxygen species (oxidative damage), could also participate to a lesser extent.

“These alterations are still present in the animals over time, even when the metabolic stress due to hypercaloric intake has disappeared. In addition, the dysfunctions transcend other cellular components and affect new biological processes (protein transport inside the mitochondria, their assembly or subsequent degradation). As a whole, this situation supposes a much more generalized cellular stress”, detail Alba González-Franquesa (Novo Nordisk) and Pau Gama-Pérez (UB), first authors of the study.

The reason why these non-functional mitochondria are not eliminated in order to avoid this cascade of detrimental effects on the cell is still a great unknown.

“Degrading waste products—metabolites, proteins, and even entire organelles—that aren’t functional in order to prevent bigger problems is a huge challenge for the cellular machinery. Knowing the role played by the cell recycling machinery is decisive for understanding health and determining possible therapeutic targets in pathologies of metabolic origin. Our results show clear indications that there are failures in this aspect, which would help us understand the reason for this loss of metabolic plasticity”, says Pau Gama-Pérez.

Aging, metabolism and obesity

Age is a critical factor in understanding the body’s ability to respond to a hypercaloric diet. In the scientific literature, older mice have been reported to be more vulnerable to these factors than young mice.

The new work, carried out with young specimens, reinforces the hypothesis that excessive caloric intake accelerates the loss of metabolic plasticity and promotes a certain state of premature aging of adipose tissue. Thus, many of the affections described in obese animals reproduce many of these hallmarks of aging.

Furthermore, it is still unknown whether the physiological imprint described in the visceral adipose compartment is also reflected in the subcutaneous fat compartment. In the clinical setting, it is also not known how visceral fat responds in these situations and it is difficult to have biological samples obtained with minimally invasive means (especially from thin and healthy individuals to be able to contrast hypotheses).

Some of the studies that have analyzed the responses of visceral fat in patients confirm a greater vulnerability in this tissue, in which alterations very similar to those described in the new study are described.

“Deciphering whether this same footprint remains in humans who have been able to reverse obesity would mean an important advance in understanding its consequences and, above all, in the design of therapeutic strategies,” the experts explain.

“Our work shows some preliminary data from an investigation carried out from a bariatric surgery in two phases, with significant weight loss and metabolic improvement between the two interventions to which the patients underwent. The magnitude of the changes in gene expression after these enhancements could tell us some similarities to what we observed in our preclinical study. In any case, it is essential to design robust studies that can address this issue as precisely as possible in obese patients, to improve their health and quality of life”, concludes the research team.

The study is titled “Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.” And it has been published in the academic journal Redox Biology. (Source: UB)