Key protein identified in fat function and obesity-related problems

Human fat is a complex, plastic, dynamic, metabolic and endocrine tissue. As the main responsible for the storage and channelling of excess energy, it performs crucial functions for health. Obesity or ageing affect the proper functioning of this paradigmatic tissue. A research team at the Girona Biomedical Research Institute (IDIBGI) is studying the molecular mechanisms responsible for this loss of function, the collapse of the adipose cell (adipocyte), and the appearance of diseases commonly associated with obesity, and has discovered that placophilin-2 (PKP2), better known for its relationship with heart disease, is involved at this turning point.

The results, published in Nature Communications, describe for the first time the role of PKP2 in the function of adipose cells that make up the adipose tissue, body fat. Until now, this protein had been extensively studied for its role in genetically caused heart conditions, but its function in adipose tissue had never been analysed before. The study, led by Dr. Francisco José Ortega, Miguel Servet researcher in the Nutrition, Eumetabolism and Health group at IDIBGI and CIBEROBN, points out that PKP2 is deficient in the adipose tissue of people with obesity. This deficiency breaks the molecular dynamics of the adipocyte and leads to its senescence, in other words, to its premature death. "This is a key phenomenon to better understand the dysfunction of adipose tissue in people with obesity," explains Dr. Ortega.

"Obesity is a condition, not a disease as such," says the researcher, who adds: "The problem is that fat cells are not able to manage all this excess energy that comes from a sedentary lifestyle and inadequate diets. They do their best, but at a certain point they collapse. Then, instead of absorbing, buffering and protecting, the fat tissue stops functioning properly, increasing the risk of diseases commonly associated with obesity".

The discovery of the role of the PKP2 protein in this process provides a better understanding of the functioning of the adipose cell and the pathophysiology of obesity. "The work shows that the presence of PKP2 is important for maintaining adipose cell viability. When it fails in the fat of people with obesity, the cell cycle stops, and the fat cell goes into senescence, accentuating the typical inflammation of this condition and the risk of suffering health problems," says Dr. Ortega. "In contrast, if the obese patient loses weight, the expression levels of this protein recover, the cycle is reactivated, and the adipocytes leave the risk zone," concludes the researcher.

The study was carried out in collaboration with the Monzino Cardiology Centre - IRCCS in Milan (Italy), the Phillips University of Maburg and the Max Delbrück Center for Molecular Medicine (Germany), the Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), and the Pablo de Olavide University in Seville (Spain), and its first author is Aina Lluch, a pre-doctoral researcher in the same Nutrition, Eumetabolism and Health group at IDIBGI. The group is led by Dr. José Manuel Fernández-Real, principal investigator at IDIBGI and CIBEROBN, head of the Endocrinology Section at the Dr. Josep Trueta Hospital in Girona and professor at the University of Girona (UdG).

About IDIBGI

IDIBGI is a biomedical research institute that is part of the CERCA system of the Generalitat de Catalunya, in Spain, dedicated to translational, clinical and epidemiological research aimed at improving health and care of people. The Institute is made up of 22 groups that carry out research in six health areas: cardiovascular and respiratory, oncohematology, metabolism and inflammation, neurosciences, mental health and medical imaging. In addition to having its own research staff, the IDIBGI manages the research carried out by health professionals from the Dr. Josep Trueta and Santa Caterina Hospitals, the Catalan Health Institute (ICS) in Girona, the Institute of Health Care Assistance (IAS), the Catalan Institute of Oncology (ICO) in Girona, and the Institute of Diagnostic Imaging (IDI).

Reference article: Lluch, A., Latorre, J., Serena-Maione, A. et al. Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence. Nat Commun 14, 5106 (2023).

DOI: https://doi.org/10.1038/s41467-023-40596-0