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Bone marrow adipocytes persist in storing fat even when energy runs out: solving this old enigma

The main function of white adipocytes is to store lipids (fatty acids) from the diet and release them when the body needs energy (caloric restriction). This release leads to a decrease in their size. In humans, 10% of the total fat mass is present in the bone marrow. Surprisingly, the bone-marrow adipocytes do not decrease in size with even prolonged caloric restriction as in anorexia. This old observation remained unexplained until now. The research team lead by Prof. Catherine Muller-Staumont from the Institute of Pharmacology and Structural Biology (IPBS - CNRS/University Toulouse III - Paul Sabatier) has just deciphered this enigma by showing that these cells lack one of the major enzymes involved in the release of fatty acids (a pathway called lipolysis). Moreover, this study shows that these cells have a specific lipid metabolism centered around cholesterol, which could have important consequences for nearby cells such as blood or bone cells, and therefore for certain hematological diseases or osteoporosis. These results are published in the journal Cell Reports on January 28th, 2020.

muller_cell_report2020-fig.jpgBM-Ads do not express MAGL, which prevents them from responding to the caloric restriction.
When energy is needed, lipolysis is activated in subcutaneous adipocytes, which allows the release of fatty acids and leads to a reduction in their size. BM- Ads lack lipolytic activity due to the absence of MAGL expression and therefore do not release fatty acids, which allows the maintenance of the BM-Ad mass in condition of energy demand. 
 

Unlike other adipose depots, bone marrow adipocytes (BM-Ad) do not decrease in size in energy deprivation (caloric restriction) even when prolonged as in anorexia. This release of fatty acids (or lipolysis) is used by the body to feed, when needed, energy-demanding cells such as the liver, muscles or heart. Why do BM-Ads not participate towards this global effort of adipose tissue?

 

To solve this physiological enigma, the researchers obtained BM-Ads and subcutaneous adipocytes (SC-Ad) from the same patients in collaboration with the Orthopedic Surgery Department of the Toulouse University Hospital (Prof. Nicolas Reina). First observation, nothing distinguishes these cells morphologically. BM-Ads, like SC-Ads, are round cells containing a single lipid droplet that occupies most of the cell. However, an exhaustive analysis of their protein content (in collaboration with the group of Odile Schiltz's "Proteomics and Mass Spectrometry of Biomolecules" from IPBS) shows that BM-Ads and SC-Ads are very different cells. In particular, BM-Ads do not express one of the major proteins of lipolysis (which is the mechanism of release of fatty acids), monacylglycerol lipase (MAGL). In BM-Ads, the induction of lipolysis, for example by adrenaline, activates receptors and intracellular messengers, but the absence of MAGL acts as a final lock that prevents fatty acids release. These results therefore explain, for the first time, why under energy demand conditions, BM-Ads do not supply fatty acids to the body and do not decrease in size. 

 

What is the use of maintaining this fat depot even in caloric restriction? The bone marrow is the site of many processes that are very important in human physiology, such as hematopoiesis (formation of blood cells) or bone renewal. Protecting this adipose tissue would allow it to be used (and preserved) for neighboring cells at the expense of other cells in the body. Their function would therefore be more local than global and another argument supports this hypothesis. In the same study, the researchers showed that BM-Ads, unlike other adipocytes, express many proteins involved in cholesterol metabolism (transport, synthesis and release). Cholesterol could have many functions in the surrounding cells such as the building of their membranes, their growth and cell signaling. The goal of future studies is now is to understand the signals that contribute to the release of this cholesterol and its use. This discovery could also have important consequences in oncology because the bone marrow is the site of the development of certain hematological malignancies such as leukemia and bone metastases. A better understanding of this specific metabolism of BM-Ads could lead to the identification of new therapeutic targets in these diseases.
 

This work was carried out in collaboration with the Department of Orthopedic Surgery (Pierre-Paul Riquet Hospital, Toulouse University Hospital), the Institute of Metabolic and Cardiovascular Diseases (Inserm/University Toulouse III - Paul Sabatier) and the Cancer Research Center of Toulouse (Inserm/University Toulouse III - Paul Sabatier) and benefited from the financial support of the Fondation de France and the Fondation pour la Recherche Médicale.

Reference

Human bone marrow is comprise of adipocytes with specific lipid metabolism 
Camille Attané # *, David Estève #, Karima Chaoui, Jason S. Iacovoni, Jill Corre, Mohamed Moutahir, Philippe Valet, Odile Schiltz, Nicolas Reina, Catherine Muller * Cell Reports, January 28th, 2020.

Contacts

Researcher IPBS: Prof. Catherine Muller | Catherine.Muller@ipbs.fr | 06 22 77 78 
Press IPBS : Francoise Viala | Communication@ipbs.fr | 06 01 26 52 59