Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
UMass Metabolic Network; Program in Molecular Medicine
Cell Biology | Cellular and Molecular Physiology | Endocrinology | Nutritional and Metabolic Diseases
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.
Cell signalling, Metabolic diseases
DOI of Published Version
Nature. 2018 Mar 29;555(7698):673-677. doi: 10.1038/nature26138. Epub 2018 Mar 21. Link to article on publisher's site
Ghorpade, Devram S.; Ozcan, Lale; Zheng, Ze; Nicoloro, Sarah M.; Shen, Yuefei; Chen, Emily; Bluher, Matthias; Czech, Michael P.; and Tabas, Ira, "Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance" (2018). University of Massachusetts Medical School Faculty Publications. 1487.