Macrophages as new therapeutic target to address obesity-related diseases

Macrophages are immune system cells that control inflammation and tissue function in addition to being crucial in the early response to microbial infection. Since it aids in the repair of damaged tissue, inflammation is a natural physiological response.

However, if it is not treated properly, it can develop into chronic inflammation, which is the root cause of several diseases, including the metabolic syndrome linked to obesity, type 2 diabetes, and cardiovascular disease.

The metabolic needs of macrophages vary depending on the organ in which they dwell, according to a study from the Centro Nacional de Investigaciones Cardiovasculares (CNIC). These cells, in other words, adjust to the requirements of the organ in which they are found.

The study gives us a better understanding of how macrophages regulate their metabolism according to the organ in which they reside. In addition, our results reveal a vulnerability of macrophages that contributes to chronic inflammatory diseases and that could be exploited therapeutically for the treatment of conditions associated with obesity and metabolic syndrome, such as cardiovascular disease.”

Dr David Sancho, Study Leader and Associate Professor and Group Leader, Immunobiology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III

On February 3^rd, 2023, an article based on the findings was published in the journal Immunity.

Immune cells known as macrophages are often found throughout the body and assist in clearing organs of any unwanted biological material. These materials can range from dangerous particles like viruses or mineral crystals to proteins or bigger complexes that form throughout development.

Macrophages are crucial for eliminating dead cells, which helps with tissue regeneration. According to the latest research, macrophages modify their metabolism and behavior depending on the organ they are housed in.

In tissues with abundant extracellular fat and cholesterol, such as the lungs and spleen, macrophages adapt their metabolism to degrade these fats through mitochondrial respiration. In tissues with abundant extracellular fat and cholesterol, such as the lungs and spleen, macrophages adapt their metabolism to degrade these fats through mitochondrial respiration.”

Dr Stefanie Wculek, Study First Author and Postdoctoral Researcher, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III

She further added, “Using genetic or pharmacological methods to disrupt mitochondrial respiration, mitochondria can be eliminated from lung and spleen, whereas the macrophages in other organs, which don’t depend on mitochondrial respiration, survive.”

The macrophages found in body fat, or adipose tissue, provide another illustration.

Dr Sancho stated, “Macrophages residing in the body fat of a person of normal weight are unaffected by mitochondria-disrupting treatments because their metabolism is less dependent on mitochondrial respiration. This is because the fat cells, called adipocytes, are fully functional, leaving the macrophages in a resting state.”

“However, in obese individuals, the excess fat surpasses the capacity of the adipocytes, and the resident macrophages become activated, converting into inflammatory cells that promote the development of insulin resistance, type 2 diabetes, and fatty liver,” he continued.

However, this modification to adipose tissue macrophages also leaves them open to attack.

Dr Sancho explained, “The activated macrophages depend on mitochondrial respiration to process the excess fat, and this makes them vulnerable to therapeutic interventions, including pharmacoligical inhibitors of mitochondrial respiration.”

The Immunity study demonstrates that activating mitochondrial respiration destroyed these proinflammatory macrophages, halting the development of obesity, type 2 diabetes, and fatty liver (the main elements of metabolic syndrome) in a model mouse.

The researchers concluded that this discovery paves the door for new therapies for diseases associated with obesity and metabolic syndrome, such as cardiovascular disease.