Poster Presentation ANZOS-Breakthrough Discoveries Joint Annual Scientific Meeting 2018

Fatty acid binding protein 4 inhibitor corrects metabolic disturbance in MKR mouse of Type 2 diabetes (#216)

Lili Huang 1 , Weizhuo Dominique Tan 1 , Chengjian Wang 2 , Zhengxiang Huang 1 , Johannes D. Veldhuis 3 , Shanli Zhu 4 , Chen Chen 1
  1. School of Biomedical Sciences, The University of Queensland, St lucia, QUEENSLAND, Australia
  2. Department of Endocrinology, ChongQing General Hospital, ChongQing, China
  3. Department of Medicine, Endocrine Research Unit, Mayo Clinic, Rochester, MN , USA
  4. Department of Microbiology and immunology, Wenzhou Medical University, Wenzhou, China

Fatty acid binding protein 4 (FABP4) is one of the key adipokines that can serve as an important biomarker predicting the risk of developing metabolic syndrome, type 2 diabetes (T2DM) and atherosclerosis (1). Genetic deficiency of FABP4 improves glucose homeostasis and reduces atherosclerosis in mouse models (2). The associated underlying mechanisms seem to be pleiotropic and request further characterization.

Here we reported that inhibition of FABP4 by a small molecule compound, BMS309403, corrected metabolic disturbance in a lean Type 2 diabetic MKR mouse model. Oral application of BMS309403 (15mg/kg) in MKR mice for 10 weeks improved insulin sensitivity and glucose tolerance (ITT AUC 896.3±107.3mmol/l·min vs 688±115.1 mmol/l·min and GTT 1741±250.4 mmol/l·min vs 1459±239.6 mmol/l·min, vehicle vs BMS309403) regardless of an increase in adipose fat mass (gonadal fat 0.28±0.02g vs 0.41±0.04; inguinal fat 0.28±0.01 vs 0.39±0.04g and brown fat 0.12±0.01 vs 0.22±0.02). These changes correlate well with an increase in genes responsible for lipogenesis (ppar gamma) and glucose transport (glu4) in adipose tissue, and a reduction of gluconeogenesis gene in muscle and liver (g6pases). In addition, treatment of BMS309403 significantly increased heat production alongside an increase in genes responsible for transcriptional activation of brown adipocytes (ucp-1 and pgc1-alpha). Furthermore, inhibition of FABP4 tends to alleviate age-associated decline of pulsatile growth hormone (GH) secretion in MKR mice (total GH 358.1± 36.18ng/ml·min vs 181.4± 54.46 ng/ml·min, vehicle mice, pre vs post treatment; and 469.1±61.94 ng/ml·min vs 392.6±32.94 ng/ml·min, BMS309403 treated mice, pre vs post treatment).

To conclude, inhibition of FABP4 improves glucose homeostasis in MKR mice, possibly by re-balancing fat/glucose metabolism and promoting adipose browning. The corresponding improvement in metabolism in diabetic MKR mice may also contribute to the relief of age-associated decline in GH secretion.

This work was supported by the Australian NHMRC and UQ.