Format

Send to

Choose Destination
Nature. 2018 Mar 29;555(7698):673-677. doi: 10.1038/nature26138. Epub 2018 Mar 21.

Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance.

Author information

1
Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
2
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
3
Proteomics Shared Resource in the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA.
4
Herbert Irving Comprehensive Cancer Center Proteomics Shared Resource, Columbia University Medical Center, New York, New York 10032, USA.
5
Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
6
Department of Pathology & Cell Biology and Department of Physiology, Columbia University Medical Center, New York, New York 10032, USA.

Abstract

Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

PMID:
29562231
PMCID:
PMC6021131
DOI:
10.1038/nature26138
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center