Understanding the Origin and Behavior of Ectopic LipIds eXcess depots: the OBELIX study

Obesity is one of the fastest growing health issues worldwide, representing a global public health concern. When overfeeding exceeds the abilityof subcutaneous adipose tissue (SAT) to expand, lipid spillover promotes fat storage in the visceral adipose tissue (VAT) and in ectopic sites. Mounting evidencesattribute to ectopic fat deposition (EFD) in organs, such as the liver, skeletal muscle and pancreas, a prominent role in the pathophysiology of metabolic diseases.However, the exact mechanism of EFD development and how it drives metabolic impairment are not fully understood. Many cellular and molecular pathways havebeen proposed as potential candidates. Among them, circulating adipose tissue-derived stem cells (ASCs) are particularly attractive, as they can reconstituteadipose tissue (AT) depots in vitro and in vivo. Intriguingly, the release of CXCR4-expressing ASCs from SAT in response to overfeeding promotes EFD in theskeletal muscle driving metabolic perturbations in mice, but whether this operates in humans is unclear. In parallel, pharmacological enhancement of cyclicguanosine monophosphate through phosphodiesterases (PDE) inhibition has shown beneficial effects in metabolic disorders. In vitro and in vivo studies indicatethat PDE5 inhibition may affect adipogenesis and ameliorate white AT quality. However, the role of PDE5 in the homeostasis on AT need to better characterized. Anemerging role is also played by the PTEN/PI3K/Akt pathway in adipocyte growth and differentiation, as mouse models with PTEN downregulation in AT display ATredistribution and ectopic fat accumulation.
AIMS. The proposal wishes to understand the origin and fate of EFD and how it drives metabolic disturbances. To achieve this challenging task, we will use anintegrated multidisciplinary translational approach spanning from basic to clinical research. The study aims to unravel how EFD develop via ASC traffic and throughspecific molecular targets, thereby allowing the future development of new therapeutic approaches against metabolic diseases. To this end, we will investigate: 1)the role of circulating human adipocyte precursors in the redistribution of AT in people with obesity; 2) the identification of tissue-resident human ASC pathwaysresponsible for EFD; 3) the role of PDE5 and PTEN in the initiation and progression of EFD using mouse models; 4) Contribution of mouse and human adipocyteprogenitors obtained from various sources in the generation and progression of EFD through in vivo transplantation assays.
IMPACT. This proposal has the potential to improve our understanding of the biology EFD and counter metabolic derangements. In view of the dramatic impact ofobesity and its complications on affected people, healthcare systems, and society, identification of new druggable targets for halting the surge of the obesitypandemic is of primary importance of the entire scientific community.