Table_2_Leptin Receptors in RIP-Cre25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice.XLSX

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.

瘦素(Leptin)是由脂肪组织分泌的强效内分泌激素，可在不依赖胰岛素的情况下调控全身广泛的代谢过程，包括糖代谢与脂代谢。中枢瘦素信号通路可通过多种机制降低胰岛素缺乏啮齿类动物(rodents)的高血糖(hyperglycemia)，其中包括改善血脂异常(dyslipidemia)。然而，介导瘦素抗血脂异常效应的特异性神经元仍未被确定。本研究发现，在由胰岛素2(Ins2)基因启动子区域短片段驱动的Cre重组酶(Cre recombinase)阳性神经元（RIP-Cre25Mgn神经元）中表达的瘦素受体(leptin receptors, LEPRs)，是中枢瘦素信号通路逆转胰岛素缺乏小鼠血脂异常、进而改善高血糖的必要条件。敲除RIP-Cre25Mgn神经元中的LEPRs，可完全阻断瘦素在胰岛素缺乏小鼠中的降糖效应。进一步研究显示，与野生型(wild-type)对照小鼠相比，RIP-Cre25Mgn神经元缺失LEPRs的胰岛素缺乏小鼠（RIP-CreΔLEPR小鼠）的血液与肝脏脂质水平更高；且向脑内注射瘦素无法抑制该类胰岛素缺乏RIP-CreΔLEPR小鼠的血脂异常。向脑内注射瘦素联合通过抑制甘油三酯脂肪酶活性来降低血脂的阿昔莫司(acipimox)，可使胰岛素缺乏的RIP-CreΔLEPR小鼠恢复正常血糖水平，这表明循环脂质过量是此类小鼠高血糖的驱动因素。综上，本研究数据证实，RIP-Cre25Mgn神经元中的LEPRs可通过改善血脂异常，以不依赖胰岛素的方式显著介导瘦素的降糖作用。