A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

Calvin C Chan, Isaac T W Harley, Paul T Pfluger, Aurelien Trompette, Traci E Stankiewicz, Jessica L Allen, Maria E Moreno-Fernandez, Michelle S M A Damen, Jarren R Oates, Pablo C Alarcon, Jessica R Doll, Matthew J Flick, Leah M Flick, Joan Sanchez-Gurmaches, Rajib Mukherjee, Rebekah Karns, Michael Helmrath, Thomas H Inge, Stuart P Weisberg, Sünje J PampDavid A Relman, Randy J Seeley, Matthias H Tschöp, Christopher L Karp, Senad Divanovic

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Abstract

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

Original languageEnglish
Article number2911
JournalNature Communications
Volume12
Issue number1
Number of pages16
ISSN2041-1723
DOIs
Publication statusPublished - 18 May 2021

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