Abstract 17776: Protection From Obesity and Systemic Insulin Resistance by Hepatocyte Growth Factor in Mice

Abstract

Background: Obesity and related disorders constitute the greatest threat to global human health. Circulating hepatocyte growth factor (HGF) level is known to increase in a diverse variety of inflammatory diseases. No exception for obesity, diabetes mellitus (DM), it is reported that its level is positively correlated with body mass index and is known to be increased in patients with metabolic syndrome. However, the role of HGF in obesity and insulin resistance is poorly understood.

Methods and Results: To examine the role of HGF in obesity, cardiac specific HGF overexpressing mice (HGFTG), with twice the serum HGF level found in WT mice, were used. HGFTG and WT were fed a high fat diet (HFD) for 14weeks. It was observed that HGFTG mice were resistant to diet-induced obesity (DIO) even daily food intake of HGFTG was higher than WT. Intraperitoneal glucose and insulin tolerance test (ipGTT/ipITT) revealed that enhanced glucose uptake in HGFTG (P<0.01). Insulin stimulation (5U/kg i.p.) analysis revealed that activation of insulin signaling was strongly down-regulated in liver, skeletal muscle, and epididymal adipose tissue in HFD-fed WT, however, it was preserved in HGFTG. Additionally, qRT-PCR analysis revealed that mRNA level of TNF-a, MCP-1, F4/80 in epididymal adipose tissue was dramatically increased in HFD fed WT, whereas it was significantly attenuated in HGFTG (P<0.01). An anti-HGF antibody (α-HGFAb) injection model was employed to examine loss-of-function of HGF under HFD feeding. The administration of 400μ g/kg/wk of α-HGFAb significantly increased body weight. The α-HGFAb group showed a significant rise in fasting glucose level and plasma insulin level (P<0.05). ipGTT and ipITT revealed that injection of α-HGFAb exacerbates impaired glucose tolerance and insulin resistance (P<0.05). Insulin stimulation analysis revealed that α-HGFAb systemically down-regulated insulin signaling.

Conclusion: Present study demonstrated that HGF attenuates DIO and insulin resistance in mice model. It is suggested that increased circulating level of HGF play a beneficial role under pathological condition of obesity and its related disorders. HGF might thus exhibit therapeutic potential in improving insulin resistance and hyperglycemia in type 2 diabetes.