A BAFF/APRIL axis regulates obesogenic diet-driven weight gain
Calvin C. Chan, Isaac T. W. Harley, Paul T. Pfluger, Aurélien Trompette, Traci E. Stankiewicz, Jessica L. Allen, Maria E. Moreno‐Fernandez, Michelle S. M. A. Damen, Jarren R. Oates, Pablo C. Alarcon, Jessica Doll, Matthew J. Flick, Leah M. Flick, Joan Sánchez-Gurmaches, Rajib Mukherjee, Rebekah Karns, Michael A. Helmrath, Thomas H. Inge, Stuart P. Weisberg, Sünje Johanna Pamp, David A. Relman, Randy J. Seeley, Matthias H. Tschöp, Christopher L. Karp, Senad Divanovic
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.