Abstract: Objective To investigate the possible mechanisms of glucagon- like peptide 1 receptor agonists (GLP-1Ra) induced weight loss. Methods High fat diet induced obese c57BL/6 mice were divided into normal control group (N,n=8), high fat feeding group (HF, n=32) and GLP-1Ra group treated with GLP-1Ra (liraglutide 200 μg/(kg·d) or 400 μg/(kg·d）for 8 weeks). Changes of body weight, blood glucose and three acyl glycosides (TG) levels were observed in three groups. HE staining was used to observe the morphological changes. Immunofluorescence staining and real-time PCR were used to measure the expression of UCP-1. Furthermore, the expression of PGC-1α in protein level was observed to explore the possible mechanism of GLP-1Ra induced browning in white fat (WAT). Results After 8-week liraglutide (Lira) administration, the body weights were significantly reduced in obese mice (P < 0.05). The levels of blood glucose and TG were significantly higher in HF group than those in N group, which reduced significantly in Lira (200 μg·kg-1) and Lira (400 μg·kg-1) administration groups (P < 0.05). HE staining showed adipocytes in perirenal and inguinal subcutaneous adipose tissue partly acquired brown-like morphological characteristics. The expression levels of UCP-1 protein and mRNA and PGC-1α protein were elevated in adipse tissues, which increased more in Lira (400) than those in Lira (200, P < 0.05). Conclusion GLP-1Ra can induce weight loss through white fat browning by activation of UCP-1.

Key words: diabetes mellitus, type 2, overweight, disease models, animal, GLP-1Ra, glucagon-like peptide-1, uncoupling protein-1, adipocyte browning, Liraglutide