They find a new therapeutic target to treat diseases associated with obesity

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

Macrophages are essential in the initial response to infections and also regulate proper tissue function and inflammation.

A team from the National Center for Cardiovascular Research (CNIC) found 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 body in which they are located. This discovery “allows us to better understand how the macrophage regulates its metabolism depending on the organ where it resides”, explains David Sancho, leader of the CNIC Immunobiology laboratory and responsible for the study published in the journal Icommunity.

“In addition, it exposes us to a vulnerability of macrophages that contribute to chronic inflammatory diseases, which could be therapeutically explored in the approach to pathologies associated with obesity and metabolic syndrome, such as cardiovascular diseases”, points out the scientist.

Under normal conditions, macrophages 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 proteins or larger complexes that appear during development. They are also important for destroying dead tissue cells, facilitating organ renewal.

In this work it is revealed that macrophages adapt their cellular metabolism and their 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 metabolism, dependent on mitochondrial activity to break down these fats through mitochondrial respiration”, says Stefanie Wculek, first author . article.

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In these tissues, explains the researcher, “macrophages depend on mitochondrial respiratory activity and, if this activity suffers genetic or pharmacological interference, macrophages die in the lung or spleen, but survive in other organs where they do not have this metabolic dependence”. .”

In obese people, excess fat overwhelms normal adipocyte activity and macrophages are activated and become inflammatory cells that promote the development of insulin resistance, type 2 diabetes and fatty liver.

David Sancho, study leader

For example, adds Sancho, “the macrophages that are located in the body fat or adipose tissue of thin people are not affected by dysfunctional mitochondria because these cells have less metabolic activity dependent on mitochondria such as adipocytes (fat cells), leaving macrophages in 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 fatty liver.”

prevent obesity

But as research has shown, at this time, “macrophages depend on mitochondrial respiration to process this excess fat, making them vulnerable to therapeutic interventions, such as pharmacological inhibition of this mitochondrial respiration process”, highlights the immunobiologist.

Therefore, the researcher emphasizes that “the inhibition of mitochondrial respiration in these pro-inflammatory 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, conclude the researchers, this discovery opens the door to a new therapeutic route for some diseases associated with obesity and metabolic syndrome, such as cardiovascular diseases.

Reference

Wculek, S. et al. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity (2023).

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