ESPE Abstracts (2016) 86 P-P1-459

Erythropoietin Activates Classical Brown Adipose Tissue Through the Erythropoietin Receptor/STAT3 Pathway, Improving Obesity and Glucose Homeostasis in High Fat Diet-induced Obese Mice

Kazuki Kodoa, Hisakazu Nakajimaa, Satoru Sugimotoa, Ikuyo Itoha, Fukuhara Syotaa, Keiichi Shigeharab, Taichiro Nishikawaa, Jun Moria, Kitaro Kosakaa & Hajime Hosoia

aDepartment of Paediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan, bDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

Background, aims and objectives: We hypothesized that classical brown adipose tissue (cBAT) could play a crucial role in the anti-obesity effects of erythropoietin (EPO). Our study highlights the mechanism in which EPO treatments could upregulate energy expenditure and improve glucose homeostasis through cBAT in obese mice fed with a high-fat diet (HFD).

Method: C57BL/6J mice had been fed with HFD since the age of 4 weeks (HFD mice). We administered recombinant human EPO (200 IU/kg) to some HFD mice intraperitoneally, three times per week for 4 weeks (HFD+EPO mice). Blood glucose, serum insulin and FGF21 were monitored and an intraperitoneal glucose tolerance test (IPGTT) was performed on the two groups. We analyzed the interscapular BAT (iBAT) and the liver harvested from both groups using molecular biology and physiological methods.

Results: Body weight, blood glucose and serum insulin were decreased in HFD+EPO mice compared with HFD mice. Serum level of FGF21, interscapular surface temperature and oxygen consumption were higher in HFD+EPO mice in comparison with HFD mice. The IPGTT showed that the levels of blood glucose were lower in HFD+EPO mice than in HFD mice. The weight of iBAT was larger in HFD+EPO mice than in HFD mice, whereas that of white adipose tissue was decreased in HFD+EPO mice than in HFD mice. The mRNA and protein levels of UCP1, beta3ADR, PRDM16, PPARα and FGF21 in the iBAT were higher in HFD+EPO than in HFD mice. However, the mRNA and protein level of FGF21 in the liver was similar between the two groups. EPO treatment significantly stimulated phosphorylation of EPO receptor (EpoR)/STAT3 in the iBAT in a HFD condition.

Conclusion: The activation of EpoR/STAT3 pathway in the cBAT by extrinsic EPO could be an underlying mechanism of the upregulation of energy expenditure and the improvement of glucose homeostasis by upregulating the secretion of FGF21 on the cBAT in HFD mice.