Session Type: Poster Session A
Session Time: 8:30AM-10:30AM
Background/Purpose: The impact of immune mediators on weight homeostasis and systemic metabolism 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 sought to define noncanonical roles for role BAFF and the BAFF homolog, A proliferation-inducing ligand (APRIL), as regulators of systemic metabolism and weight homeostasis.
Methods: Multiple murine genetic models with variable levels of BAFF and APRIL sufficiency/overexpression were examined in the context of an in vivo model of obesogenic diet-induced obesity. Direct effects of BAFF on murine white adipose tissue and brown adipose tissue adipocytes were examined in vitro and in vivo. Whether these effects on murine metabolism were relevant to humans was assessed by examining plasma BAFF and APRIL levels with BMI change in response to bariatric surgery in obese individuals. Similarly, the direct effects on human white adipose tissue were assessed by examining the expression of orthologous human genes on white adipose tissue adipocytes in response to treatment with recombinant human BAFF and APRIL.
Results: 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 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 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. Importantly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with BMI decrease after bariatric surgery. Finally, preliminary results suggest that the critical source BAFF in these models is intestinal epithelial cells.
Conclusion: Together, our results define the BAFF/APRIL axis as a multifaceted immune regulator of weight gain and adipose tissue function. The percentage change in BAFF sufficient to modify obesity in murine models is comparable to levels that increase risk of Lupus and Multiple Sclerosis in humans. Thus, these findings will inform our understanding of the unexpected potential metabolic effects of B-cell targeted therapies in humans.
To cite this abstract in AMA style:Harley I, Chan C, Pfluger P, Aurelien T, Stankiewicz T, Allen J, Moreno-Fernandez M, Damen M, Oates J, Alarcon P, Doll J, Flick M, Flick L, Sanchez-Gurmaches J, Mukherjee R, Karns R, Helmrath M, Inge T, Weisberg S, Pamp S, Relman D, Seeley R, Tschoep M, Karp C, Divanovic S. Unappreciated Systemic Metabolic Functions of the Canonical B Cell Cytokines, BAFF and APRIL: Regulation of Lipolysis and Non-shivering Thermogenesis and Protection from Obesogenic Diet Induced Weight Gain [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 10). https://acrabstracts.org/abstract/unappreciated-systemic-metabolic-functions-of-the-canonical-b-cell-cytokines-baff-and-april-regulation-of-lipolysis-and-non-shivering-thermogenesis-and-protection-from-obesogenic-diet-induced-weight/. Accessed December 4, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/unappreciated-systemic-metabolic-functions-of-the-canonical-b-cell-cytokines-baff-and-april-regulation-of-lipolysis-and-non-shivering-thermogenesis-and-protection-from-obesogenic-diet-induced-weight/