Novel role of Fibroblast Activation Protein (FAP) in energy metabolism observed in a diet induced obesity model — ASN Events
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Novel role of Fibroblast Activation Protein (FAP) in energy metabolism observed in a diet induced obesity model (#210)

Sumaiya Chowdhury 1 , Sunmi Song 1 , Margaret G Gall 1 , Xin M Wang 1 , Denise MT Yu 1 , Kathryn A Evans 1 , Lisa Lo 2 , Charlie Zheng 1 , Nigel Turner 3 , Gregory Cooney 3 , Geoffrey W McCaughan 1 , Susan V McLennan 2 , Stephen M Twigg 2 , Mark D Gorrell 1
  1. Centenary Institute and Sydney Medical School, The University of Sydney, NSW, Australia
  2. Bosch Institute and Sydney Medical School, the University of Sydney, Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  3. Diabetes and Obesity Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, NSW, Australia

Background: Dipeptidyl peptidase IV (DPP4) inhibitors increase active incretin levels, improve glucose homeostasis and are a type 2 diabetes therapy. The role of other members of the DPP4 enzyme family in energy metabolism has not been examined.

Aim: This study investigated the role of Fibroblast Activation Protein (FAP), the closest relative of DPP4, in energy metabolism using a diet induced obesity [DIO] model.

Methods: FAP gene knockout (gko) and wild type (WT) mice were fed an ad libitum high fat diet supplemented with 5% fructose water for 20 weeks. Glucose tolerance, insulin sensitivity, serum insulin, liver fat and liver function were measured at 20 weeks.

Results: FAP gko mice showed improved glucose tolerance (GTT AUC: FAPgko: 1344±63.86; WT: 1631±31.7 mmol.min/L, p=0.01), insulin sensitivity (ITT AUC: mmol.min/L; p=0.04), circulating insulin (FAPgko: 34.1±2.9; WT: 110 ± 19.3 ng/mL; p=0.004), and HOMA-IR (FAPgko: 0.7±0.06; WT: 2.4±0.3; p=0.008) scores compared to DIO-WT mice, suggesting protection against DIO-induced impaired glucose homeostasis. FAPgko mice had less serum alanine transaminase (FAPgko: 49.5±6.2; WT: 67.6±6.5 U/L; p=0.05), hepatocellular vacuolation and total liver lipid (FAPgko: 2.2±0.3; WT: 3.8±0.9 mg/g; p=0.03), suggesting protection against DIO-induced fatty liver. The FAPgko mice had less intrahepatic mRNA of glucokinase and PPARγ, major lipogenic genes, and CD36, a gene involved in hepatic triglyceride and fatty acid uptake, and increased glucose-6-phosphatase. Also, FAPgko mice had a lower respiratory exchange ratio (vCO2/vO2) (FAPgko: 0.785 ± 0.008; WT: 0.815 ± 0.013, p=0.05), indicative of increased lipid oxidation.

Conclusion: These data suggest that FAP has important roles in glucose and lipid metabolism and suggest that FAP inhibitors might become a unique intervention for treating obesity-induced glucose intolerance, insulin resistance, type 2 diabetes and fatty liver.