Exp Clin Endocrinol Diabetes 2013; 121 - P36
DOI: 10.1055/s-0033-1336675

DPP4 shedding from human adipocytes and smooth muscle cells is mediated by metalloproteinases but not altered by inflammatory stimuli

D Röhrborn 1, J Eckel 1, H Sell 1
  • 1German Diabetes Center, Paul-Langerhans-Group Integrative Physiologie, Düsseldorf, Germany

Introduction: DPP4 has recently been identified as a novel adipokine by comprehensive proteomic profiling of the adipocyte-secretome by our group. This protease is upregulated in visceral adipose tissue of obese patients and circulating DPP4 correlates with the metabolic syndrome. The release of DPP4 is increasing during the adipocyte differentiation in vitro. DPP4 enhances the proliferation of human smooth muscle cells (hSMC) and is therefore interesting in the context of atheriosclerosis. Our aim was to understand how DPP4 release is regulated and which factors are responsible for the shedding of DPP4 from the cell membrane.

Methods: Comparing different human cell types for their DPP4 release, adipocytes and hSMC showed the highest release of DPP4 with 2000pg/mL and 300pg/mL, respectively. Both cell types were used to elucidate the shedding mechanism of DPP4. Cells were treated with different inflammatory cytokines (IL-1b, IFNgamma at 1 – 100 ng/mL and MCP-1 2 ng/mL). Furthermore, inhibitors for different classes of proteases were used to identify potential shedding enzymes. DPP4 release to the culture medium was measured by ELISA.

Results: In both adipocytes and hSMC, IL-1b, IFNgamma and MCP-1 had no significant effect on the DPP4 release. However, of the tested protease inhibitors, the general MMP inhibitor Batimastat, the serine protease-inhibitor AEBSF and the cysteine protease-inhibitor E64 showed significant reduction of DPP4 release both in adipocytes and hSMC (remaining DPP4 release in hSMC: Batimastat 50%, E64 70%, AEBSF 60%). We could observe no additive effects of AEBSF, E64 and Batimastat in combination, which suggests that the effects are not independent. Experiments to identify specific MMP, responsible for DPP4 shedding, are ongoing at the moment.

Conclusion: Our results suggest that DPP4 shedding is mediated by metalloproteinases that are dysregulated during obesity and type 2 diabetes mellitus.