ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0004

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

Isaac Harley1, Calvin Chan2, Paul Pfluger3, Trompette Aurelien4, Traci Stankiewicz5, Jessica Allen5, Maria Moreno-Fernandez5, Michelle Damen5, Jarren Oates5, Pablo Alarcon5, Jessica Doll6, Matthew Flick7, Leah Flick8, Juan Sanchez-Gurmaches9, Rajib Mukherjee9, Rebekah Karns10, Michael Helmrath11, Thomas Inge12, Stuart Weisberg13, Sunje Pamp14, David Relman15, Randy Seeley16, Matthias Tschoep17, Chris Karp18 and Senad Divanovic8, 1University of Colorado Anschutz Medical Campus, Aurora, CO, 2University of Cincinnati, Cincinnati, OH, 3Technical University of Munich, Munich, Germany, 4Le Centre hospitalier universitaire vaudois, Lausanne, Switzerland, 5Cincinnati Children's Hospital Medical Center, Division of Immunobiology, Cincinnati, OH, 6Cincinnati Children's Hospital Medical Center, Division of Immunobiology, Cincinn, OH, 7Division of Experimental Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 8Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 9Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 10Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 11Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 12Department of Surgery, Children’s Hospital Colorado, Aurora, CO, 13Columbia University Medical Center, New York, NY, USA, New York, NY, 14Danmarks Tekniske Universitet, Lyngby, Denmark, 15Department: Medicine - Med/Infectious Diseases - Stanford University, Stanford, 16Department of Surgery, Internal Medicine and Nutritional Sciences, University of Michigan, Ann Arbor, MI, 17Division of Metabolic Diseases, Technische Universität München, Munich, Germany, 18Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati

Meeting: ACR Convergence 2021

Keywords: , , , ,

Session Information

Date: Saturday, November 6, 2021

Title: B Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster (0001–0010)

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.

Disclosures: I. Harley, None; C. Chan, None; P. Pfluger, None; T. Aurelien, None; T. Stankiewicz, None; J. Allen, N/A, 12, Patent on BAFF and APRIL; M. Moreno-Fernandez, None; M. Damen, None; J. Oates, None; P. Alarcon, None; J. Doll, None; M. Flick, None; L. Flick, None; J. Sanchez-Gurmaches, None; R. Mukherjee, None; R. Karns, None; M. Helmrath, None; T. Inge, None; S. Weisberg, None; S. Pamp, None; D. Relman, None; R. Seeley, consultant to Novo Nordisk, Sanofi, Scohia, GuidePoint Consultants, Kintai Therapeutics, and Ionis., 2, Novo Nordisk, Zafgen, Astra Zeneca, Redesign Health, Ionis and Pfizer, 12, research support or equity; M. Tschoep, Novo Nordisk and ERX, 1; C. Karp, N/A, 12, Patent on BAFF and APRIL; S. Divanovic, N/A, 12, Patent on BAFF and APRIL, Janssen Research & Development, 2.

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 9). 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 .

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