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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 (US)
Article number2911
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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