MXRA8 promotes adipose tissue whitening to drive obesity

Wentong Jia,Rocky Giwa,John R. Moley,Gordon I. Smith,Max C. Petersen,Rachael L. Field, Omar Abousaway, Arthur S. Kim, Sarah R. Coffey, Stella Varnum, Jasmine M. Wright,Xinya Zhang, Samantha Krysa,Irfan J. Lodhi,Nada A. Abumrad,Samuel Klein,Michael S. Diamond,Jonathan R. Brestoff

biorxiv(2024)

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摘要
Matrix-remodeling associated 8 (MXRA8), also known as Dual immunoglobulin domain cell adhesion molecule (DICAM), is a type 1 transmembrane protein that reportedly binds the αVβ3 integrin1 and regulates the differentiation of osteoclasts2 and chondrocytes, tumor growth, T cell trafficking, and angiogenesis. MXRA8 is also an essential entry receptor for chikungunya virus and other related arthritogenic alphaviruses. We compared MXRA8 expression in 51 tissues in the Human Protein Atlas and found it is most highly expressed in white adipose tissue (WAT), however the function of MXRA8 in WAT is unknown. Here, we found that MXRA8 expression in WAT is increased in people with obesity and that this response is also observed in a mouse model of high fat-diet (HFD)-induced obesity. Single-nucleus RNA sequencing and high-dimensional spectral flow cytometry analyses revealed that MXRA8 is expressed predominantly by adipocyte progenitor (AP) cells and mature adipocytes. MXRA8 mutant primary adipocytes from inguinal (i)WAT exhibited increased expression of Uncoupling protein 1 (UCP1), a thermogenic protein expressed by beige and brown adipocytes that limits obesity pathogenesis. Indeed, MXRA8 mutant mice fed a HFD had preserved UCP1+ beige and brown adipocytes and were protected from HFD-induced obesity in a UCP1-dependent manner. Collectively, these findings indicate that MXRA8 promotes whitening of beige and brown adipose tissues to drive obesity pathogenesis and identify MXRA8 as a possible therapeutic target to treat obesity and associated metabolic diseases. ### Competing Interest Statement JRB, MSD, and WJ are co-inventors on a pending patent application related to this work. JRB is a member of the Scientific Advisory Board for LUCA Science, Inc., has consulted for DeciBio within the past 12 months, and receives royalties from Springer Nature Group. The other authors declare no conflicts of interest.
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