Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
Authors
Ghorpade, Devram S.Ozcan, Lale
Zheng, Ze
Nicoloro, Sarah M.
Shen, Yuefei
Chen, Emily
Bluher, Matthias
Czech, Michael P.
Tabas, Ira
Document Type
Journal ArticlePublication Date
2018-03-21Keywords
Cell signallingMetabolic diseases
Cell Biology
Cellular and Molecular Physiology
Endocrinology
Nutritional and Metabolic Diseases
Metadata
Show full item recordAbstract
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.Source
Nature. 2018 Mar 29;555(7698):673-677. doi: 10.1038/nature26138. Epub 2018 Mar 21. Link to article on publisher's site
DOI
10.1038/nature26138Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29256PubMed ID
29562231Related Resources
ae974a485f413a2113503eed53cd6c53
10.1038/nature26138