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Background: Studies on chemerin/chemokine-like receptor-1 have mainly focused on adipose and liver with the intestinal tissues largely overlooked. In this study conducted on obese mice, we have explored: 1) CMKLR1 expression in the ileums; 2) CMKLR1 inhibitor α-NETA on body weight and intestinal mucosa integrity hence the impact on hepatic steatosis and pathway involved. Methods: Nineteen male C57BL/6 mice were randomly divided into five groups: normal diet group (ND), high-fat diet group (HFD), HFD + α-NETA group (NETA), HFD + PD98059 group (PD) and HFD + α-NETA + PD98059 group (NETA + PD). Mice were fed either with a chow diet or HFD for 12 weeks. At 12th week, mice of ND were put on the diet as before; mice of NETA received daily treatments of α-NETA (30 mg/kg) via gavage; mice of PD received daily treatment of PD98059 via tail vein injection; mice of NETA + PD received daily treatment of α-NETA + PD98059, all for another 4 weeks. At the time intervention ended, mice were sacrificed. The body weight, the liver pathologies were assessed. Ileal CMKLR1 mRNA was evaluated by rtPCR; ZO-1, ERK1/2 protein expression of ileal tissues by western blotting; liver TNF-α and serum endotoxin by Elisa. Results: More weight gains in mice of HFD than ND (37.90 ± 3.00 g) vs (24.47 ± 0.50 g), P = 0.002; α-NETA reduced the body weight (33.22 ± 1.90 g) vs (37.90 ± 3.00 g), P = 0.033; and further reduced by NETA + PD98059: (31.20 ± 1.74 g) vs (37.30 ± 4.05 g), P = 0.032. CMKLR1 mRNA expression was up-regulated in ileum in group HFD compared with ND and down-regulated by α-NETA. Steatosis was only alleviated in group PD + NETA with less weight gain. No impact of α-NETA on ileal ZO-1 or pERK with western blotting, and no endotoxin level changes were detected. TNF-α was higher in group HFD than in group ND, while no significant difference between other groups. Conclusions: CMKLR1 mRNA was up-regulated in the ileum of obese mice and down-regulated by α-NETA along with a body weight control collaborating with ERK inhibitor PD98059. Steatosis was alleviated in a weight dependent way. α-NETA has no influence on intestinal mucosal integrity and no impact on steatohepatitis progression. [ABSTRACT FROM AUTHOR]