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

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)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 sensitivity6–8. 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.

Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease

“…In a recent study, liver‐specific DPP‐4 transgenic mice showed elevation of systemic DPP‐4 enzyme activity, hypercholesterolaemia and an increased adipose fat mass with inflammation and hepatic steatosis, suggesting that increased expression of DPP‐4 in the liver not only promotes NAFLD but also contributes to hepatic insulin resistance . A very recent study demonstrated that obesity stimulates the production and secretion of soluble DPP‐4 by hepatocytes, which promotes adipose tissue inflammation and insulin resistance in the liver via caveolin‐1, suggesting that sDPP‐4 may be involved in crosstalk between the liver and adipose tissue as a hepatokine . However, inhibition of circulating DPP‐4 enzyme activity by sitagliptin (a DPP‐4 inhibitor) did not block adipose tissue inflammation or improve hepatic insulin resistance .…”

“…NAFLD/NASH may be associated with elevation of serum sDPP‐4, since hepatocytes show high expression of DPP‐4 and could act as the main source of circulating sDPP‐4 in patients with NAFLD/NASH . A very recent study performed in mice showed that obesity stimulated hepatocytes to produce and secrete soluble DPP‐4, which promoted adipose tissue inflammation and insulin resistance in the liver through caveolin‐1, suggesting that sDPP‐4 may play a role in crosstalk between the liver and adipose tissue . Therefore, reducing the serum level of sDPP‐4 may be associated with improvement of liver dysfunction in patients with type 2 diabetes and NAFLD.…”

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

“…). Insulin resistance (IR) and NAFLD are crucially linked; IR leads to reduced glucose uptake in adipocytes and muscles, and hepatocytes can secrete dipeptidyl peptidase 4, which promotes adipose tissue inflammation and IR …”

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

“…Four PAR family members have been identified to date, designated PAR1-PAR4. Activated PAR2 is involved in various (patho)physiologies, including vasoregulation, cell growth, cancer, inflammation, obesity, and nociception [2,3]. PAR2 couples with Ga i/o , Ga q/11 and Ga 12/13 subtypes, in turn, regulating various signaling pathways, including phospholipases, c-Jun N-terminal kinase, ERK1/2, phosphatidylinositol 3-kinase, adenylyl cyclase, protein kinase C, protein kinase A (PKA), and members of the src family of tyrosine kinases [1,2].…”