The study highlights two important concepts: the importance of receptor localization at the cell surface and the notion of “metabolically healthy” obesity. These concepts are linked by a protein called 'Endospanin 1' (also known as Leprot or OBRGRP).
Obesity is a crucial research topic in Europe, addressed by the European Union's research and innovation programs (Horizon Europe). Obesity is a condition that often causes health problems, such as steatosis (accumulation of fat in the liver), type 2 diabetes, and low-grade chronic inflammation, leading to cancers and cardiovascular diseases. However, some individuals with obesity do not necessarily develop metabolic disorders, highlighting the notion of “metabolically healthy obesity”, whose existence is controversial and mechanisms are unclear.
CD36, which has attracted much attention, is a pleiotropic receptor initially described as a lipid-binding receptor and is primarily known for its role in lipid transport in adipose tissue, particularly in fat cells called “adipocytes”. Usually, the overall amount of this protein or its messenger RNA is measured to monitor its function, but its exact localization within the cell is not always taken into account.
The study reveals that the trafficking protein, Endospanin 1, regulates the amount of CD36 on the surface of fat cells by retaining CD36 inside the cells. In the absence of Endospanin 1, levels of CD36 receptor are increased at the surface of adipocytes, which promotes fat absorption by adipocytes and thus prevents the deleterious accumulation of fat in other organs. In line with these observations, mice deleted for Endospanin 1, fed a high-fat diet, develop obesity but with fewer health problems (better glucose tolerance, less fat in the liver, less inflammation, better insulin sensitivity). Interestingly, this correlation has also been observed in humans, suggesting that a low level of Endospanin 1 may help promote “metabolically healthy” obesity in humans.
This work highlights the importance of assessing the levels of receptors and transmembrane proteins on the cell surface, a variable that is often underestimated but can nevertheless have significant consequences in pathology.
Research on the molecular mechanisms underlying obesity and its metabolic alterations remains an important area of investigation. It is essential to understand the disease, develop effective prevention and treatment strategies, improve public health and reduce the economic and social impacts related to overweight and obesity.
The study was funded by:
European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 241592 and from the European Union’s Horizon Europe Research and Innovation Program under grant agreement 101080465 (OBELISK project), Agence Nationale de la Recherche ANR-12-JSV1-0011, ANR-15-CE14-0025, ANR-21-CE14-0041, Department Hospitalo Universitaire (DHU) AUTHORS, Fondation pour la recherche médicale, Inserm, CNRS.
Reference
Roca-Rivada A, Do Cruzeiro M, Denis RG, Zhang Q, Rouault C, Rouillé Y, Launay JM, Cruciani-Guglielmacci C, Mattot V, Clément K, Jockers R, Dam J. Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations. JCI Insight. 2024 Apr 2;9(9):e168418. doi: 10.1172/jci.insight.168418.
