期刊
NATURE
卷 555, 期 7698, 页码 673-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature26138
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资金
- NATIONAL CANCER INSTITUTE [P30CA013696] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007343, R01HL140554, P01HL087123, R01HL075662] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK063608, R01DK106045, R01DK103047] Funding Source: NIH RePORTER
- NCI NIH HHS [P30 CA013696] Funding Source: Medline
- NHLBI NIH HHS [R01 HL075662, R01 HL140554, P01 HL087123, T32 HL007343] Funding Source: Medline
- NIDDK NIH HHS [R01 DK103047, P30 DK063608, R01 DK106045] Funding Source: Medline
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)(1). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs)(2,3). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance4,5, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity(6-8). 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.
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