ESPE Abstracts (2015) 84 FC8.6

Metabolic Effects of ADP355, Protein-Based Adiponectin Receptor Agonist, on Mice with High-Fat Diet Induced Fatty Liver Disease

Eun Byoul Leea,b, Tae Hyuk Kimc, Woo Jung Leec, Ah Reum Kwonc, Hyun Wook Chaec, Duk Hee Kimd & Ho-Seong Kimb,c

aDepartment of Pediatrics, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Inchon, Republic of Korea; bDepartment of Medicine, Yonsei University Graduate School, Seoul, Republic of Korea; cDepartment of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; dSowha Children’s Hospital, Seoul, Republic of Korea

Background: Adiponetin is considered a protective hormone exhibiting beneficial effects against insulin resistance, cardiovascular disease, and cancer. Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic component of insulin resistance. Pharmacological activation of adiponectin signaling might be helpful for treatment of NAFLD, but it is difficult to develop the whole adiponectin protein as a drug because the C-terminal globular domain of adiponectin is extremely insoluble and the peptide fragments are large. ADP355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-Dser-Phe-Ala-DSer-NH2), a peptide-based adiponectin receptor agonist, inhibits the growth of AdipoR1/AdipoR2-positive cancer cell lines.

Objective and hypotheses: ADP355 act through AdipoR1 mainly, we thought it would activate AMPK pathway in the liver and improve NAFLD. We treated ADP355 on mice with high-fat diet (HFD) induced fatty liver disease to investigate the metabolic effects of ADP355.

Method: Twenty mice were randomly divided into standard diet (SD, n=5) and HFD (n=15) group. After 12 weeks, HFD-fed mice were randomized into three groups for ADP355 treatment (none, 0.5, and 1 mg/kg per day) for 4 weeks. Intraperitoneal glucose tolerance test (IPGTT) were done in all mice before and after 27 days of ADP355 treatment. One day after IPGTT, mice were sacrificed and livers were weighed. Hematoxylin and eosin-stained sections analysed to establish the type and the degree of steatosis. Hepatic mRNA expression level of sterol regulatory element binding protein 1c (SREBP1c), acetyl-CoA carboxylase (ACC), fatty-acid synthase (FAS), palmitoyl transterase 1 (CPT1), acyl-CoA oxidase (ACO), and aldehyde oxidase 1 (AOX1) were measured.

Results: Body weights were significantly lower in ADP355 treatment group, but liver weight, liver weight/body weight ratio, and area under curve of glucose level in IPGTT showed no significant difference. Grade of steatosis, SREBP1c, FAS, ACC, and AOX were significantly lower in ADP355 treatment groups than HFD group.

Conclusion: ADP355 ameliorate HFD induced weight-gain and steatosis of liver in mice by decreasing de novo lipogenesis and stimulating fatty acid oxidation through AMPK pathway, but have no effect on insulin resistance.

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