Adipose tissue inflammation and vascular dysfunction
Final Report Abstract
Obesity is the hallmark of the metabolic syndrome and predisposes patients to the development of major chronic metabolic diseases including type 2 diabetes mellitus and cardiovascular disease. The association between the epidemics of obesity and the metabolic syndrome has promoted research on the endocrine link between expanded adipose tissue, deregulated lipid and glucose homeostasis, vascular dysfunction, and other metabolic complications. Most importantly, adipose tissue is an active endocrine organ releasing a large variety of the so-called adipokines. Although the crosstalk of adipose tissue with cells in the vascular wall, such as smooth muscle cells is not yet fully understood, many proteins released from adipose tissue are associated with the development of cardiovascular diseases. Using a comprehensive protein profiling of adipocyte-conditioned medium, Dipeptidyl peptidase 4 (DPP4) was identified as an adipokine related to obesity and the metabolic syndrome. DPP4 expression and release is increased in the obese state and further augmented in patients with type 2 diabetes. In this context, DPP4 is predominantly present in visceral adipose tissue where its expression is already increased in lean patients with impaired glucose tolerance. DPP4 release from adipose tissue occurs in a metalloproteinase-dependent manner and is hypoxia-sensitive. In order to provide insight into a role for DPP4 for the crosstalk between adipose tissue and the vascular wall, we characterized a novel DPP4-induced signaling cascade in smooth muscle cells. DPP4 activates the MAPK- and NF-κB signaling pathway in a proteaseactivated receptor 2-dependent manner leading to pro-atherogenic changes in smooth muscle cells like increased proliferation and inflammation. Considering that DPP4 is an adipokine with increased circulating levels in obesity, it can be speculated that DPP4 may act in a para- or endocrine fashion on the vascular wall which could potentially contribute to inflammation in this setting. In summary, the results obtained in this project contribute to the understanding of the endocrine function DPP4 in the obese state. Our in vitro data obtained in smooth muscle cells extend the current view of DPP4 action beyond the incretin system towards direct endocrine action and shed light on cardiovascular effects of DPP4-inhibitors.
Publications
- Adipose DPP4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care, 36:4083-90, 2013
Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, Knoefel WT, Dietrich A, Fielding BA, Arner P, Frayn KN, Eckel J
- Adipocyte-derived factors impair insulin signaling in differentiated human vascular smooth muscle cells via the upregulation of miR-143. BBA Mol Bas Dis, 1842:275-83, 2014
Blumensatt M*, Wronkowitz N*, Wiza C, Cramer A, Mueller H, Rabelink MJ, Hoeben RC, Eckel J, Sell H, Ouwens M
(See online at https://doi.org/10.1016/j.bbadis.2013.12.001) - Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Letters, 588:3870-7, 2014
Röhrborn D, Eckel J, Sell H
(See online at https://doi.org/10.1016/j.febslet.2014.08.029) - Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. BBA Mol Bas Dis, 1842:1613-21, 2014
Wronkowitz N, Görgens SW, Romacho T, Villalobos LA, Sánchez-Ferrer CF, Peiró C, Sell H, Eckel J
(See online at https://doi.org/10.1016/j.bbadis.2014.06.004)
