PI3K signalling pathway revealed as potential drug target for obesity

Researchers have discovered the signalling pathways responsible for the development of a type of adipose tissue macrophage (ATM) in obesity, which prevents lipotoxicity – the process whereby fat molecules are deposited in non-adipose tissues.

The study was conducted by scientists at the Medical University (MedUni) of Vienna, CeMM (Research Center for Molecular Medicine of the Austrian Academy of Sciences) and University of Graz, all Austria, in collaboration with researchers from Poland, Germany and Australia. 

According to the researchers, a central element in the development of obesity is adipose tissue, which comprises fat cells – so-called adipocytes, which are specialised to store fat – and macrophages. 

In this study, the researchers studied the PI3K signalling pathway. This is a major metabolic regulator, as it regulates fat storage and plays a major role in the cellular reaction to the hormone insulin. In obesity, diminished insulin action or insulin resistance leads to type II diabetes, which is linked to high blood glucose levels.

Gernot Schabbauer, senior author of the study, has been studying the PI3K signalling pathway in immune cells for several years now: “The key role of PI3K in metabolic processes is proven but its role in adipose tissue macrophages was hitherto unclear.”

Julia Brunner, co-lead author of the study, added: “ATMs are like Dr Jekyll and Mr Hyde – in obesity, they can either be good or bad. We assumed that an active PI3K signalling pathway could tip the balance in favour of ‘good’.”

Using techniques such as multicolour flow cytometry, lipidomics, cellular respiration tests and several animal models, the scientists discovered that sustained activity of the PI3K signalling pathway can tip the balance within macrophages for the better: this produces specialised ATMs, which are characterised by increased numbers of macrophage receptor with collagenous structure (MARCO) scavenger receptors on their surface.

“We discovered that these MARCO-expressing ATMs are professional lipid scavengers. These cells absorb fat MARCO-dependently and break it down, thereby preventing it from finding its way into the bloodstream,” explained Andrea Vogel, co-lead author of the study.

Omar Sharif, co-senior author of the study, said: “Metabolic syndrome and lipotoxicity are characteristic features of obesity. Our work indicates that a higher lipid intake and improved energy metabolism of the ATMs helps to maintain systemic metabolic health. This can have far-reaching impacts for a number of metabolic diseases.”

The team say that subsequent studies will now be conducted to establish whether PI3K signalling can also have a lasting influence on the ATM population in humans as well. 

This study was published in Nature Metabolism.