New therapeutic target in macrophages identified for the treatment of obesity-related diseases

A team of researchers at the CNIC has discovered that the metabolic requirements of macrophages differ depending on the organ in which they reside. In other words, these cells adapt to the needs of the organ in which they are located.

The new study reveals that macrophages adapt their metabolism and function to the organ in which they reside. “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,” explained first author Dr. Stefanie Wculek. “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.”

Another example is provided by the macrophages located in body fat, or adipose tissue. “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,” said the study leader. “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.”

But this change in adipose tissue macrophages also makes them vulnerable. The Immunity study shows that inhibition of mitochondrial respiration killed these proinflammatory macrophages, preventing the progression of obesity, type 2 diabetes, and fatty liver (the key components of metabolic syndrome) in an experimental mouse model.

Reference:

Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis,Immunity,doi 10.1016/j.immuni.2023.01.011