Osteopontin is a key player for local adipose tissue macrophage proliferation in obesity.
Recent findings point towards an important role of local macrophage proliferation also in obesity-induced adipose tissue inflammation that underlies insulin resistance and type 2 diabetes. Osteopontin (OPN) is an inflammatory cytokine highly upregulated in adipose tissue (AT) of obese and has repeatedly been shown to be functionally involved in adipose-tissue inflammation and metabolic sequelae. In the present work, we aimed at unveiling both the role of OPN in human monocyte and macrophage proliferation as well as the impact of OPN deficiency on local macrophage proliferation in a mouse model for diet-induced obesity.



The impact of recombinant OPN on viability, apoptosis, and proliferation was analyzed in human peripheral blood monocytes and derived macrophages. Wild type (WT) and OPN knockout mice (SPP1KO) were compared with respect toin vivoadipose tissue macrophage andin vitrobone marrow-derived macrophage (BMDM) proliferation.



OPN not only enhanced survival and decreased apoptosis of human monocytes but also induced proliferation similar to macrophage colony stimulating factor (M-CSF). Even in fully differentiated monocyte-derived macrophages, OPN induced a proliferative response. Moreover, proliferation of adipose tissue macrophages in obese mice was detectable in WT but virtually absent in SPP1KO. In BMDM, OPN also induced proliferation while OPN as well as M-CSF-induced proliferation was similar in WT and SPP1KO.



These data confirm that monocytes and macrophages not only are responsive to OPN and migrate to sites of inflammation but also they survive and proliferate more in the presence of OPN, a mechanism also strongly confirmedin vivo. Therefore, secreted OPN appears to be an essential player in AT inflammation, not only by driving monocyte chemotaxis and macrophage differentiation but also by facilitating local proliferation of macrophages.
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Matteo
M
Tardelli
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; FH Campus Wien, University of Applied Sciences, Department Health, Section Biomedical Science, Vienna, Austria.
Karina
K
Zeyda
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Veronica
V
Moreno-Viedma
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Bettina
B
Wanko
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Nicole G
NG
Grün
AFFiRiS AG, Vienna, Austria.
Günther
G
Staffler
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria.
Maximilian
M
Zeyda
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: thomas.stulnig@meduniwien.ac.at.
Thomas M
TM
Stulnig
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity; D053495:Osteopontin / Q000502:physiology*
C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D053495:Osteopontin
Adipose tissue; Adipose tissue macrophage; Inflammation; OPN; Obesity