The role of the phosphatidylserine receptor Brain-specific angiogenesis inhibitor 1 (BAI1) in diet induced obesity
Gastroenterology
Immunology
Final Report Abstract
More than 2 billion people worldwide are either overweight or obese and at least 2.4 million deaths per year are directly related to excess body weight. These numbers show that obesity has reached epidemic proportions, but effective treatments are still lacking. As adipocyte cell death is a prominent feature in response to high fat diet feeding, we hypothesized that interfering at the level of dead cell clearance could open up new therapeutic routes. More precisely, we hypothesized that boosting apoptotic cell clearance via the phosphatidylserine receptor BAI1 might ameliorate weight gain and improve metabolic parameters in response to high fat diet. However, we quickly realized that this hypothesis could not be upheld, as BAI1 was not expressed in the adipose tissue. Due to some preliminary data that suggested that artificial overexpression of a human BAI1 transgene in adipocytes yields beneficial effects in a model of diet-induced obesity, we still had hope that some of the downstream signaling following sensing of phosphatidylserine via BAI1 is active in adipocytes and that other receptors might signal through this pathway. Indeed, we found that AXL, a member of the TAM family of engulfment receptors, is expressed in preadipocytes and that AXL is both necessary and sufficient for phosphatidylserine sensing and apoptotic cell uptake. Next we analyzed the role of phosphatidylserine in adipocyte differentiation: We found that a steady percentage of viable preadipocytes exposes phosphatidylserine during adipogenesis and that masking of phosphatidylserine completely blocked differentiation of preadipocytes into mature white adipocytes. Viable phosphatidylserine exposure is often mediated by caspase-independent scramblases and we identified TMEM16F as a candidate that is expressed in preadipocytes. Indeed, TMEM16F knockout mice show lower body weight, lower weight of the subcutaneous inguinal fat pad and are resistant to diet-induced obesity. Similar to masking of phosphatidylserine, knockout of TMEM16F in preadipocytes abrogated their capacity to differentiate into mature white adipocytes. In conclusion, we identified phosphatidylserine exposure and sensing as a critical factor in adipocyte differentiation and we aim to understand the precise sequence of events and the underlying molecular signature in the near future.
Publications
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(See online at https://doi.org/10.1016/j.celrep.2019.10.104) - Living on the Edge: Efferocytosis at the Interface of Homeostasis and Pathology. Immunity. 2019 May 21;50(5):1149-1162
Morioka S, Maueröder C, Ravichandran KS
(See online at https://doi.org/10.1016/j.immuni.2019.04.018) - A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism. Cell Reports. 2021 Sep 21;36(12):109748
Catrysse L, Maes B, Mehrotra P, Martens A, Hoste E, Martens L, Maueröder C, Remmerie A, Bujko A, Slowicka K, Sze M, Vikkula H, Ghesquière B, Scott CL, Saeys Y, van de Sluis B, Ravichandran K, Janssens S, van Loo G
(See online at https://doi.org/10.1016/j.celrep.2021.109748) - Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death & Differentiation. 2021 Nov;28(11):3125-3139
Ackermann M, Anders HJ, Bilyy R, Bowlin GL, Daniel C, De Lorenzo R, Egeblad M, Henneck T, Hidalgo A, Hoffmann M, Hohberger B, Kanthi Y, Kaplan MJ, Knight JS, Knopf J, Kolaczkowska E, Kubes P, Leppkes M, Mahajan A, Manfredi AA, Maueröder C, Maugeri N, Mitroulis I, Muñoz LE, Narasaraju T, Naschberger E, Neeli I, Ng LG, Radic MZ, Ritis K, Rovere- Querini P, Schapher M, Schauer C, Simon HU, Singh J, Skendros P, Stark K, Stürzl M, van der Vlag J, Vandenabeele P, Vitkov L, von Köckritz-Blickwede M, Yanginlar C, Yousefi S, Zarbock A, Schett G, Herrmann M
(See online at https://doi.org/10.1038/s41418-021-00805-z)
