Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, have shown how immune system cells, macrophages, have a key role in the regulation of obesity and the findings could be useful in the development of new treatments for people with obesity and overweight, and for some associated pathologies, including fatty liver disease and type 2 diabetes. It explains how the activation of the mitochondrial metabolism of macrophages in response to oxidative stress due to excess nutrients contributes to fatty tissue inflammation and obesity.
The study, ‘Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity’, published in Nature Metabolism, was led by CNIC researchers directed by Drs José Antonio Enríquez and David Sancho. It was completed in collaboration with the David Geffen School of Medicine and the Department of Medicine/Division of Cardiology of the University of California, Los Angeles (UCLA), the University of Eastern Finland and the Kuopio University Hospital (Finland); and the University of Salamanca and the Complutense University of Madrid.
"In recent decades, several studies have verified that fatty tissue macrophages facilitate an anti-inflammatory and reparative environment in normal conditions. This contributes to deactivating any processes altering the normal functioning of these tissues. These are known as anti-inflammatory or 'type M2' macrophages," explained Enríquez. "The M2 macrophages interpret that there are stress signals, normally arising in response to infection and they foster inflammation as a defines mechanism.”
These inflammation processes sourced to macrophages are responsible for the emergence of fatty tissue alterations, and "are the origin of obesity and the metabolic syndrome associated to cardiovascular disorders, fatty liver disease and type 2 diabetes," he added.
This means that, as a response to the excess nutrients created by a high-fat diet, "macrophages change their function and support inflammatory processes, forming 'type M1' proinflammatory macrophages."
The research analyzed how macrophage metabolic changes regulate this inflammatory process, which underlies obesity and the metabolic syndrome. The new findings, said Dr Rebeca Acín-Pérez (currently at UCLA), "reveal how the detection by macrophages of oxidative danger signals - known as reactive oxygen species - leads to mitochondrial metabolism changes of these immune cells, needed to distinguish them from an M1 proinflammatory type."
This oxidative stress, she clarified, is found in morbidly obese patients, and it seems to be related to a high-fat diet, commonplace in the inadequate Western diet.
One of the conditions of this study, added Sancho, is that it proves that when this oxidative stress is reduced, "it ameliorates some of the harmful parameters associated with obesity."
In previous studies, CNIC scientists had found that the Fgr protein is decisive in regulating one of the complexes of the transport chain of mitochondrial electrons - the II complex - in response to this oxidative stress and to benefit the generation of signals (cytokines and metabolites) fostering immune responses.
Salvador Iborra claimed that this study "proves that this same molecular mechanism regulates the conversion process of an anti-inflammatory macrophage (M2) governing the function of the tissue to a proinflammatory macrophage (M1), where lipid droplets accumulate. A balance between both types of M2/M1 macrophages is crucial for the proper functioning of the body."
Although inflammation is a normal body response and it is beneficial to face acute and transitory threats, it is very damaging when it becomes persistent or chronic, even in low-grade inflammation scenarios. The researchers explain that this happens in obesity and the metabolic syndrome, and it leads to increased cardiovascular mortality and diabetes.
The information contained in this paper proves that, in the absence of the Fgr protein, the liver increases its ability to eliminate fat by generating ketone bodies (chemical compounds produced by ketogenesis, a process using body fats as an energy source), which are eliminated in the urine, and that this further enhances the alterations of obesity to the glucose metabolism (type 2 diabetes).
The results, found in mice, have been corroborated by human cohorts, where the authors found a stark correlation of Fgr and the negative consequences of obesity.
The researchers concluded that their data suggest the potential of using specific Fgr protein inhibitors to treat obese and/or metabolic syndrome patients. The goal would be reducing the associated inflammation, thereby improving the parameters associated with these illnesses, like fatty liver and type 2 diabetes, and contributing to raise patients' life expectancy and quality.