A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation

Jixin Zhong, Xiaoquan Rao, Jeffrey Deiuliis, Zachary Braunstein, Vimal Narula, Jeffrey Hazey, Dean Mikami, Bradley Needleman, Abhay R. Satoskar, Sanjay Rajagopalan

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

Original languageEnglish (US)
Pages (from-to)149-157
Number of pages9
JournalDiabetes
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Abdominal Obesity
Dendritic Cells
Macrophages
Inflammation
Adenosine Deaminase
Obesity
Dipeptidyl-Peptidase IV Inhibitors
T-Lymphocytes
Incretins
Intra-Abdominal Fat
Extracellular Matrix Proteins
Type 2 Diabetes Mellitus
Lipopolysaccharides
Adipose Tissue
Monocytes
Rodentia
Cell Proliferation
Cytokines
Peptides
Membranes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Zhong, J., Rao, X., Deiuliis, J., Braunstein, Z., Narula, V., Hazey, J., ... Rajagopalan, S. (2013). A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes, 62(1), 149-157. https://doi.org/10.2337/db12-0230

A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. / Zhong, Jixin; Rao, Xiaoquan; Deiuliis, Jeffrey; Braunstein, Zachary; Narula, Vimal; Hazey, Jeffrey; Mikami, Dean; Needleman, Bradley; Satoskar, Abhay R.; Rajagopalan, Sanjay.

In: Diabetes, Vol. 62, No. 1, 01.01.2013, p. 149-157.

Research output: Contribution to journalArticle

Zhong, J, Rao, X, Deiuliis, J, Braunstein, Z, Narula, V, Hazey, J, Mikami, D, Needleman, B, Satoskar, AR & Rajagopalan, S 2013, 'A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation', Diabetes, vol. 62, no. 1, pp. 149-157. https://doi.org/10.2337/db12-0230
Zhong, Jixin ; Rao, Xiaoquan ; Deiuliis, Jeffrey ; Braunstein, Zachary ; Narula, Vimal ; Hazey, Jeffrey ; Mikami, Dean ; Needleman, Bradley ; Satoskar, Abhay R. ; Rajagopalan, Sanjay. / A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. In: Diabetes. 2013 ; Vol. 62, No. 1. pp. 149-157.
@article{05f44a25eb3142e58d7aecf8a6047472,
title = "A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation",
abstract = "Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.",
author = "Jixin Zhong and Xiaoquan Rao and Jeffrey Deiuliis and Zachary Braunstein and Vimal Narula and Jeffrey Hazey and Dean Mikami and Bradley Needleman and Satoskar, {Abhay R.} and Sanjay Rajagopalan",
year = "2013",
month = "1",
day = "1",
doi = "10.2337/db12-0230",
language = "English (US)",
volume = "62",
pages = "149--157",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "1",

}

TY - JOUR

T1 - A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation

AU - Zhong, Jixin

AU - Rao, Xiaoquan

AU - Deiuliis, Jeffrey

AU - Braunstein, Zachary

AU - Narula, Vimal

AU - Hazey, Jeffrey

AU - Mikami, Dean

AU - Needleman, Bradley

AU - Satoskar, Abhay R.

AU - Rajagopalan, Sanjay

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

AB - Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

UR - http://www.scopus.com/inward/record.url?scp=84872041568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872041568&partnerID=8YFLogxK

U2 - 10.2337/db12-0230

DO - 10.2337/db12-0230

M3 - Article

VL - 62

SP - 149

EP - 157

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 1

ER -