Abstract：Objective Based on leptin signal transduction negative feedback mechanism, a non-obese leptin resistance mouse model was constructed to investigate whether high leptin level could induce peripheral leptin resistance and its mechanism of action. Methods C57 BL/6J mice with normal diet were selected as the test subjects, and then grouped as follows (each n=6): mice in the 8-week model group were intraperitoneally injected with leptin 5 μg/(g·d) for 8 weeks, mice in the 14-week model group were intraperitoneally injected with leptin 5 μg/(g·d) for 14 weeks, and mice in the control group were intraperitoneally injected with same amount of normal saline once a day for 14 successive weeks. Blood and liver tissues were collected after the end of the experiment, serum leptin concentration was measured by ELISA. Western blot was used to measure the protein expression levels of leptin signal transduction feedback factor suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) as well as the protein expression and phosphorylation levels of the major signaling molecules in signal transducer and activator of transcription-3 (STAT3) pathway, mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3-kinase (PI3K) signaling pathway. Results The body weight of mice in the two model groups was lower than that of the control group, no obesity was found. As compared with the control group, serum leptin concentration in the mice of the 14-week model group significantly increased (P<0.05), and then the mice developed hyperleptinemia. Serum leptin concentration was also elevated in the 8-week model group, but the difference was not statistically significant. No statistically significant differences were found in the protein expression levels of liver SOCS3 (F=0.057, P=0.945) and PTP1B (F=3.192, P=0.070) as well as in the protein expression and phosphorylation levels of Janus kinase 2 (JAK2)(F=1.239, P=0.318), STAT3 (F=3.276, P=0.066), p38MAPK (F=2.217, P=0.143), extracellular regulated protein kinase 1/2 (ERK1/2) (F=3.080, P=0.076), c-Jun N-terminal kinase (JNK) (F=1.534, P=0.248), PI3K (F=2.220, P=0.143) and protein kinase B (PKB/Akt) (F=0.519, P=0.605) between the two model groups and the control group, Conclusions Long-term exogenous leptin injection have no effect on the expression of leptin signaling pathways and leptin signal transduction feedback factors (like SOCS3 and PTP1B) in peripheral tissues of mice, hyperleptinemia alone cannot induce peripheral leptin resistance in mice.
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