Obesity is one of the main risk factors for the development of diabetes and other metabolic disorders, such as hepatic steatosis, a condition characterized by fat accumulation in the liver that can progress to more severe diseases, including cirrhosis and liver cancer.
A team of researchers from the University of Padua and the Veneto Institute of Molecular Medicine (VIMM) has discovered a new mechanism through which a high-fat diet alters the intestinal barrier and triggers systemic inflammation, increasing the risk of metabolic diseases such as type 2 diabetes — one of the world’s major health emergencies, affecting more than half a billion people globally and about 4 million in Italy.
The study, published in the journal Diabetes, identifies a key role for the enzyme PADI4 and a process known as NETosis.
“We observed that a typical Western diet, rich in fats, induces an immune response in neutrophils — white blood cells responsible for defending the body against bacterial and fungal infections,” explained Mattia Albiero, first author of the study and researcher at the Department of Surgical, Oncological and Gastroenterological Sciences of the University of Padua and at VIMM. “Neutrophils release structures called NETs, which in turn compromise the intestinal barrier, facilitating the spread of bacterial components into the bloodstream and promoting systemic inflammation.”
The researchers conducted experiments on animal models and human adipose tissue samples, demonstrating that diet-induced NETosis leads to an increase in intestinal permeability, resulting in the spread of inflammatory signals throughout the body. In particular, mice lacking the PADI4 enzyme, or in which the enzyme was pharmacologically inhibited, were protected from the negative effects of a high-fat diet.
“This discovery opens the way to new therapeutic strategies,” added Gian Paolo Fadini, Full Professor of Endocrinology at the Department of Medicine of the University of Padua, Director of the Unit for Metabolic Diseases and Diabetology at the University Hospital, and Head of the Experimental Diabetology Laboratory at VIMM. “Pharmacological inhibition of PADI4 could represent a new approach to preventing metabolic complications associated with obesity, such as type 2 diabetes and hepatic steatosis.”
The publication highlights the importance of understanding the mechanisms underlying these interactions in order to develop new preventive and therapeutic strategies. The implications of this research are highly significant for advancing our understanding of metabolic diseases and suggest a potential therapeutic target to counteract the negative effects of overeating and obesity.