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. Pamp; David A. Relman; Randy J. Seeley; Matthias H. Tschöp; Christopher L. Karp; Senad Divanovic

doi:10.1038/s41467-021-23084-1

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 journal › Article › peer-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 language	English (US)
Article number	2911
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23084-1
State	Published - Dec 2021
Externally published	Yes

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-23084-1

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Chan, C. C., Harley, I. T. W., Pfluger, P. T., Trompette, A., Stankiewicz, T. E., Allen, J. L., Moreno-Fernandez, M. E., Damen, M. S. M. A., Oates, J. R., Alarcon, P. C., Doll, J. R., Flick, M. J., Flick, L. M., Sanchez-Gurmaches, J., Mukherjee, R., Karns, R., Helmrath, M., Inge, T. H., Weisberg, S. P., ... Divanovic, S. (2021). A BAFF/APRIL axis regulates obesogenic diet-driven weight gain. Nature communications, 12(1), [2911]. https://doi.org/10.1038/s41467-021-23084-1

Chan, Calvin C. ; Harley, Isaac T.W. ; Pfluger, Paul T. ; Trompette, Aurelien ; Stankiewicz, Traci E. ; Allen, Jessica L. ; Moreno-Fernandez, Maria E. ; Damen, Michelle S.M.A. ; Oates, Jarren R. ; Alarcon, Pablo C. ; Doll, Jessica R. ; Flick, Matthew J. ; Flick, Leah M. ; Sanchez-Gurmaches, Joan ; Mukherjee, Rajib ; Karns, Rebekah ; Helmrath, Michael ; Inge, Thomas H. ; Weisberg, Stuart P. ; Pamp, Sünje J. ; Relman, David A. ; Seeley, Randy J. ; Tschöp, Matthias H. ; Karp, Christopher L. ; Divanovic, Senad. / A BAFF/APRIL axis regulates obesogenic diet-driven weight gain. In: Nature communications. 2021 ; Vol. 12, No. 1.

@article{b6f944cf74204a519257c3d9131e101a,

title = "A BAFF/APRIL axis regulates obesogenic diet-driven weight gain",

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.",

author = "Chan, {Calvin C.} and Harley, {Isaac T.W.} and Pfluger, {Paul T.} and Aurelien Trompette and Stankiewicz, {Traci E.} and Allen, {Jessica L.} and Moreno-Fernandez, {Maria E.} and Damen, {Michelle S.M.A.} and Oates, {Jarren R.} and Alarcon, {Pablo C.} and Doll, {Jessica R.} and Flick, {Matthew J.} and Flick, {Leah M.} and Joan Sanchez-Gurmaches and Rajib Mukherjee and Rebekah Karns and Michael Helmrath and Inge, {Thomas H.} and Weisberg, {Stuart P.} and Pamp, {S{\"u}nje J.} and Relman, {David A.} and Seeley, {Randy J.} and Tsch{\"o}p, {Matthias H.} and Karp, {Christopher L.} and Senad Divanovic",

note = "Funding Information: This study was supported, in part, by American Diabetes Association (ADA) 1-18-IBS-100 (to S.D.); CCHMC Pediatric Diabetes and Obesity Center (to S.D., M.H., and T.H.I.); NIH R01DK099222 (to S.D.); NIH R01DK099222-S1 (associated with S.D. and M.E.M.F. and J.R.O); NIH R21AI139829 and R21AI139829-S1 (associated with S.D.); DoD W81XWH2010392 (associated with S.D.); Cincinnati Children{\textquoteright}s Research Foundation (CCRF) Endowed Scholar Award (to S.D.); American Heart Association (AHA) 17POST33650045 (to M.E.M.F.); ADA 1-19-PMF-019 (to M.E.M.F.); AHA 18CDA34080527 (to J.S.-G); AHA 19POST34380545 (to R.M.); NIH R01AI075159 (to C.L.K.); NIH T32AI118697 and T32GM063483-14 (associated with C.C.C.); Albert J. Ryan Foundation Fellowship (to I.T.W.H.); NIH HD07463 and GM063483 (associated with I.T.W.H.); NIH K08DK122130 (associated with S.P.W.); PHS Grant P30 DK078392 Pathology of the Digestive Disease Research Core Center at CCHMC (associated with S.D.); and CCHMC Trustee Award (to J.S.-G). Thomas C. and Joan M. Merigan Endowment at Stanford University (to D.A.R.). Marie Sk{\l}odowska Curie training network “ChroMe” grant H2020-MSCA-ITN-2015-675610 (to M.H.T. and P.T.P.); German Center for Diabetes Research (DZD) (to M.H.T. and P.T.P.); Initiative and Networking Fund of the Helmholtz Association (to M.H.T. and P.T.P.); Helmholtz-Israel-Cooperation in Personalized Medicine (to P.T.P.); Helmholtz Initiative for Personalized Medicine (iMed) (to M.H.T.); and Helmholtz Portfolio Program “Metabolic Dysfunction” (to M.H.T.). We thank Dr. Burden for providing Mlc1f-cre mice. The Cd180tm1a(KOMP)Wtsi targeted ES cells used for this research project were generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (www.komp.org). We thank Dr. Rajewsky, Dr. Bram, and Dr. Erickson for providing BAFF/APRIL axis transgenic mouse lines used in these studies. We also thank Dr. Daniel Giles, Matthew Lawson, and the CCHMC Pediatrics Diabetes and Obesity Center team for technical assistance. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-23084-1",

language = "English (US)",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Chan, CC, Harley, ITW, Pfluger, PT, Trompette, A, Stankiewicz, TE, Allen, JL, Moreno-Fernandez, ME, Damen, MSMA, Oates, JR, Alarcon, PC, Doll, JR, Flick, MJ, Flick, LM, Sanchez-Gurmaches, J, Mukherjee, R, Karns, R, Helmrath, M, Inge, TH, Weisberg, SP, Pamp, SJ, Relman, DA, Seeley, RJ, Tschöp, MH, Karp, CL & Divanovic, S 2021, 'A BAFF/APRIL axis regulates obesogenic diet-driven weight gain', Nature communications, vol. 12, no. 1, 2911. https://doi.org/10.1038/s41467-021-23084-1

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

In: Nature communications, Vol. 12, No. 1, 2911, 12.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

AU - Chan, Calvin C.

AU - Harley, Isaac T.W.

AU - Pfluger, Paul T.

AU - Trompette, Aurelien

AU - Stankiewicz, Traci E.

AU - Allen, Jessica L.

AU - Moreno-Fernandez, Maria E.

AU - Damen, Michelle S.M.A.

AU - Oates, Jarren R.

AU - Alarcon, Pablo C.

AU - Doll, Jessica R.

AU - Flick, Matthew J.

AU - Flick, Leah M.

AU - Sanchez-Gurmaches, Joan

AU - Mukherjee, Rajib

AU - Karns, Rebekah

AU - Helmrath, Michael

AU - Inge, Thomas H.

AU - Weisberg, Stuart P.

AU - Pamp, Sünje J.

AU - Relman, David A.

AU - Seeley, Randy J.

AU - Tschöp, Matthias H.

AU - Karp, Christopher L.

AU - Divanovic, Senad

N1 - Funding Information: This study was supported, in part, by American Diabetes Association (ADA) 1-18-IBS-100 (to S.D.); CCHMC Pediatric Diabetes and Obesity Center (to S.D., M.H., and T.H.I.); NIH R01DK099222 (to S.D.); NIH R01DK099222-S1 (associated with S.D. and M.E.M.F. and J.R.O); NIH R21AI139829 and R21AI139829-S1 (associated with S.D.); DoD W81XWH2010392 (associated with S.D.); Cincinnati Children’s Research Foundation (CCRF) Endowed Scholar Award (to S.D.); American Heart Association (AHA) 17POST33650045 (to M.E.M.F.); ADA 1-19-PMF-019 (to M.E.M.F.); AHA 18CDA34080527 (to J.S.-G); AHA 19POST34380545 (to R.M.); NIH R01AI075159 (to C.L.K.); NIH T32AI118697 and T32GM063483-14 (associated with C.C.C.); Albert J. Ryan Foundation Fellowship (to I.T.W.H.); NIH HD07463 and GM063483 (associated with I.T.W.H.); NIH K08DK122130 (associated with S.P.W.); PHS Grant P30 DK078392 Pathology of the Digestive Disease Research Core Center at CCHMC (associated with S.D.); and CCHMC Trustee Award (to J.S.-G). Thomas C. and Joan M. Merigan Endowment at Stanford University (to D.A.R.). Marie Skłodowska Curie training network “ChroMe” grant H2020-MSCA-ITN-2015-675610 (to M.H.T. and P.T.P.); German Center for Diabetes Research (DZD) (to M.H.T. and P.T.P.); Initiative and Networking Fund of the Helmholtz Association (to M.H.T. and P.T.P.); Helmholtz-Israel-Cooperation in Personalized Medicine (to P.T.P.); Helmholtz Initiative for Personalized Medicine (iMed) (to M.H.T.); and Helmholtz Portfolio Program “Metabolic Dysfunction” (to M.H.T.). We thank Dr. Burden for providing Mlc1f-cre mice. The Cd180tm1a(KOMP)Wtsi targeted ES cells used for this research project were generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (www.komp.org). We thank Dr. Rajewsky, Dr. Bram, and Dr. Erickson for providing BAFF/APRIL axis transgenic mouse lines used in these studies. We also thank Dr. Daniel Giles, Matthew Lawson, and the CCHMC Pediatrics Diabetes and Obesity Center team for technical assistance. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85106181376&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-23084-1

DO - 10.1038/s41467-021-23084-1

M3 - Article

C2 - 34006859

AN - SCOPUS:85106181376

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2911

ER -

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

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