New therapeutic target in macrophages to treat diseases associated with obesity

Macrophages are cells of the immune system that, in addition to being essential in the early response to infections caused by pathogenic microbes, also regulate the proper functioning of tissues and inflammation. Inflammation is a positive phenomenon that helps to repair damaged tissue, but if it is not adequately resolved it leads to chronic inflammation that is at the origin of many pathologies, such as metabolic syndrome associated with obesity, type 2 diabetes and diseases cardiovascular.

Now, a team from the National Center for Cardiovascular Research (CNIC) in Spain has discovered that the metabolic needs of macrophages are different depending on the organ in which they reside. That is, they adapt to the needs of the organ in which they are located. This discovery, the researchers explain, “allows us to better understand how the macrophage regulates its metabolism depending on the organ in which it resides. In addition, it exposes us to a vulnerability of macrophages that contribute to chronic inflammatory diseases, which could be exploited therapeutically in the approach to pathologies associated with obesity and metabolic syndrome, as well as cardiovascular diseases”, points out Dr. David Sancho, who directs the CNIC Immunobiology laboratory and is co-author of the new study.

Macrophages are cells of the immune system, which under normal conditions are distributed throughout all tissues and serve to clean the body of any type of biological material that needs to be removed, from harmful particles such as microcrystals or viruses, to larger proteins or complexes that appear during development. They are also important for destroying dead tissue cells, facilitating organ renewal.

Images captured by electron microscope in a normal mouse lung macrophage (left) and in a mouse macrophage deficient in mitochondrial oxidative phosphorylation (right). The spiral-like structures are accumulations of fat and cholesterol. (Images: CNIC)

In the new study, published in the academic journal Immunity, it is revealed that macrophages adapt their cellular metabolism and function to the organ where they reside. “In tissues rich in extracellular fat and cholesterol, such as the lung or spleen, macrophages accommodate their metabolism and acquire a more specific one dependent on mitochondrial activity to break down these fats through mitochondrial respiration” says Dr. Stefanie Wculek , co-author of the study.

In these tissues, explains the researcher, “macrophages depend on mitochondrial respiration activity and, if this activity is genetically or pharmacologically interfered with, macrophages die in the lung or spleen, but survive in other organs where they do not have this metabolic dependence.” .”

For example, adds Dr. Sancho, “macrophages located in body fat or adipose tissue of thin people are not affected by dysfunctional mitochondria because these cells have a less mitochondria-dependent metabolic activity when adipocytes are fully functional ( fat cells), leaving macrophages in a resting state.

Instead, explains the researcher, “in obese people, excess fat exceeds the normal activity of adipocytes and macrophages are activated and become inflammatory cells that promote the development of insulin resistance, type 2 diabetes and the fatty liver”.

But as seen in this research, at this time, “macrophages depend on mitochondrial respiration to process this excess fat, which makes them vulnerable to therapeutic interventions, such as pharmacological inhibition of this mitochondrial respiration process.” highlights Dr. Sancho.

Therefore, emphasizes the researcher, we have seen that “the inhibition of mitochondrial respiration in these proinflammatory macrophages causes their death and this prevents the development of obesity, type 2 diabetes and fatty liver (metabolic syndrome) in a preclinical experimental model in mice” .

Thus, the researchers conclude, this finding opens the door to a new therapeutic pathway for some diseases associated with obesity and metabolic syndrome, such as cardiovascular diseases. (Source: CNIC)