In people living with obesity, visceral adipose tissue - located deep around the organs - can become fibrous and rigid. This phenomenon, known as fibrosis, disrupts normal fat function and contributes to metabolic complications such as insulin resistance and type 2 diabetes. A team of researchers from Sorbonne University, Inserm and AP-HP, working in the Nutriomics laboratory, has identified a new therapeutic strategy to counter the effects of fibrosis. Using two drugs already approved for other indications, they have succeeded in blocking adipose tissue fibrosis and restoring its proper function in obese mice. These results are published in the journal Cell Reports Medicine .
Adipose tissue plays a central role in controlling the body’s energy balance. The phenomenon of fibrosis in obese people alters normal fat function and plasticity. It also aggravates metabolic complications such as insulin resistance and type 2 diabetes, and acts as a brake on weight loss.
To better understand the mechanisms involved in fibrosis, the team of researchers focused on a population of cells known as CD9+ progenitors. The published study reveals that the abundance of these cells in the adipose tissue of obese patients is associated with increased fibrosis, impaired glycemic control and a higher incidence of type 2 diabetes.
Furthermore, in patients with severe obesity and type 2 diabetes, an increase in the abundance of these CD9+ progenitors prior to bariatric surgery (or obesity surgery) is associated with less metabolic improvement one year after surgery. These results therefore position CD9+ progenitors as prime therapeutic targets for locally improving fat tissue function, with potential beneficial effects on overall health.
The team then conducted a preclinical study in mice to validate this hypothesis. Using in-depth molecular analyses, the researchers identified the signaling pathways activated in these cells and tested drugs capable of inhibiting them
. The combination of two molecules already in clinical use, ninedanib (antifibrosant) and celecoxib (anti-inflammatory), proved particularly effective. Indeed, it significantly reduced the development of adipose tissue fibrosis in obese mice and improved their metabolic health.
The team also discovered that the treatment acted on mesothelial cells, specialized cells that form a protective barrier on the surface of visceral organs, but which, in the context of obesity, contribute to fibrosis on the surface of fatty tissue.
These results are promising because they are based on combination therapies already available, paving the way for rapid translation into clinical trials. Preserving or restoring the proper functioning of adipose tissue could thus be a key strategy for limiting the deleterious effects of obesity.
Combined pharmacological targeting of CD9+ progenitors alleviates obesity-induced adipose tissue fibrosis and metabolic impairment
Clémentine Rebière 1 , 7 - Ana Letícia Silveira 1 , 2 , 7 - Amanda Oliveira 1 , 2 , 7
- Jimon Boniface Abatan 1 - Cindy Rose 1 - Simon Lecoutre 1
- Gabriela Barbosa Pires Fagundes 1 , 2 - Jean Debédat 1 -
- Véronique Pelloux 1 - Jean-Christophe Bichet 4 - Judith Aron-Wisnewsky 1 , 5 -
- Karine Clément 1 , 5 , 8 Geneviève Marcelin 1 , 8 , 9
1 Sorbonne University, INSERM U1269, Nutrition and obesities: systemic approach research group, Nutriomics, Paris F-75013, France
2 Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
3 Sorbonne Université, INSERM U1135, CNRS, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris 75013, France
4 Assistance Publique Hôpitaux de Paris, Service de Chirurgie et Cancérologie Gynécologique et Mammaire, Pitié-Salpêtrière Hospital, Paris, France
5 Assistance Publique Hôpitaux de Paris, Nutrition Department, CRNH Ile de France, Pitié-Salpêtrière Hospital, Paris, France
6 Assistance Publique Hôpitaux de Paris, Visceral Surgery Department, Pitié-Salpêtrière Hospital, Paris, France
