IgG is elevated in obese white adipose tissue but does not induce glucose intolerance via Fcγ-receptor or complement

A D van Dam; L van Beek; A C M Pronk; S M van den Berg; J Van den Bossche; M P J de Winther; F Koning; C van Kooten; P C N Rensen; M R Boon; J S Verbeek; K Willems van Dijk; V van Harmelen

doi:10.1038/ijo.2017.209

IgG is elevated in obese white adipose tissue but does not induce glucose intolerance via Fcγ-receptor or complement

Int J Obes (Lond). 2018 Feb;42(2):260-269. doi: 10.1038/ijo.2017.209. Epub 2017 Aug 30.

Authors

A D van Dam^{1

2}, L van Beek^{2

3}, A C M Pronk^{2

3}, S M van den Berg⁴, J Van den Bossche⁴, M P J de Winther⁴, F Koning⁵, C van Kooten⁶, P C N Rensen^{1

2}, M R Boon^{1

2}, J S Verbeek³, K Willems van Dijk^{1

2

3}, V van Harmelen^{2

3}

Affiliations

¹ Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
² Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
³ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

PMID: 28852207
DOI: 10.1038/ijo.2017.209

Abstract

Background/objectives: In obesity, B cells accumulate in white adipose tissue (WAT) and produce IgG, which may contribute to the development of glucose intolerance. IgG signals by binding to Fcγ receptors (FcγR) and by activating the complement system. The aim of our study was to investigate whether activation of FcγR and/or complement C3 mediates the development of high-fat diet-induced glucose intolerance.

Methods: We studied mice lacking all four FcγRs (FcγRI/II/III/IV^-/-), only the inhibitory FcγRIIb (FcγRIIb^-/-), only the central component of the complement system C3 (C3^-/-), and mice lacking both FcγRs and C3 (FcγRI/II/III/IV/C3^-/-). All mouse models and wild-type controls were fed a high-fat diet (HFD) for 15 weeks to induce obesity. Glucose metabolism was assessed and adipose tissue was characterized for inflammation and adipocyte functionality.

Results: In obese WAT of wild-type mice, B cells (+142%, P<0.01) and IgG (+128% P<0.01) were increased compared to lean WAT. Macrophages of FcγRI/II/III/IV^-/-mice released lower levels of cytokines compared to wild-type mice upon IgG stimulation. Only C3^-/- mice showed reduced HFD-induced weight gain as compared to controls (-18%, P<0.01). Surprisingly, FcγRI/II/III/IV^-/- mice had deteriorated glucose tolerance (AUC +125%, P<0.001) despite reduced leukocyte number (-30%, P<0.05) in gonadal WAT (gWAT), whereas glucose tolerance and leukocytes within gWAT in the other models were unaffected compared to controls. Although IgG in gWAT was increased (+44 to +174%, P<0.05) in all mouse models lacking FcγRIIb, only FcγRI/II/III/IV/C3^-/- mice exhibited appreciable alterations in immune cells in gWAT, for example, increased macrophages (+36%, P<0.001).

Conclusions: Lack of FcγRs reduces the activity of macrophages upon IgG stimulation, but neither FcγR nor C3 deficiency protects against HFD-induced glucose intolerance or reduces adipose tissue inflammation. This indicates that if obesity-induced IgG contributes to the development of glucose intolerance, this is not mediated by FcγR or complement activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, White / metabolism*
Animals
Cells, Cultured
Complement C3 / metabolism*
Diet, High-Fat
Disease Models, Animal
Glucose Intolerance / metabolism*
Inflammation / metabolism*
Inflammation / physiopathology
Male
Mice
Mice, Knockout
Obesity / metabolism*
Obesity / physiopathology
Receptors, IgG / metabolism*

Substances

Complement C3
Fcgr2b protein, mouse
Receptors, IgG