Denroche Heather C, Kwon Michelle M, Glavas Maria M, Tudurí Eva, Philippe Marion, Quong Whitney L, Kieffer Timothy J
Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
Mol Metab. 2016 Jun 24;5(8):716-724. doi: 10.1016/j.molmet.2016.06.009. eCollection 2016 Aug.
Leptin reverses hyperglycemia in rodent models of type 1 diabetes (T1D). Direct application of leptin to the brain can lower blood glucose in diabetic rodents, and can activate autonomic efferents and non-shivering thermogenesis in brown adipose tissue (BAT). We investigated whether leptin reverses hyperglycemia through a mechanism that requires autonomic innervation, or uncoupling protein 1 (UCP1)-mediated thermogenesis.
To examine the role of parasympathetic and sympathetic efferents in the glucose-lowering action of leptin, mice with a subdiaphragmatic vagotomy or 6-hydroxydopamine induced chemical sympathectomy were injected with streptozotocin (STZ) to induce hyperglycemia, and subsequently leptin treated. To test whether the glucose-lowering action of leptin requires activation of UCP1-mediated thermogenesis in BAT, we administered leptin in STZ-diabetic Ucp1 knockout (Ucp1 (-/-)) mice and wildtype controls.
Leptin ameliorated STZ-induced hyperglycemia in both intact and vagotomised mice. Similarly, mice with a partial chemical sympathectomy did not have an attenuated response to leptin-mediated glucose lowering relative to sham controls, and showed intact leptin-induced Ucp1 expression in BAT. Although leptin activated BAT thermogenesis in STZ-diabetic mice, the anti-diabetic effect of leptin was not blunted in Ucp1 (-/-) mice.
These results suggest that leptin lowers blood glucose in insulin-deficient diabetes through a manner that does not require parasympathetic or sympathetic innervation, and thus imply that leptin lowers blood glucose through an alternative CNS-mediated mechanism or redundant target tissues. Furthermore, we conclude that the glucose lowering action of leptin is independent of UCP1-dependent thermogenesis.
瘦素可逆转1型糖尿病（T1D）啮齿动物模型中的高血糖。将瘦素直接应用于大脑可降低糖尿病啮齿动物的血糖，并可激活自主传出神经以及棕色脂肪组织（BAT）中的非寒战产热。我们研究了瘦素是否通过一种需要自主神经支配或解偶联蛋白1（UCP1）介导的产热的机制来逆转高血糖。
为了研究副交感神经和交感神经传出神经在瘦素降血糖作用中的作用，对膈下迷走神经切断或6-羟基多巴胺诱导化学性交感神经切除术的小鼠注射链脲佐菌素（STZ）以诱导高血糖，随后进行瘦素治疗。为了测试瘦素的降血糖作用是否需要激活BAT中UCP1介导的产热，我们对STZ诱导的糖尿病Ucp1基因敲除（Ucp1（-/-））小鼠和野生型对照给予瘦素。
瘦素改善了完整小鼠和迷走神经切断小鼠中STZ诱导的高血糖。同样，相对于假手术对照，部分化学性交感神经切除术的小鼠对瘦素介导的血糖降低反应并未减弱，并且在BAT中显示出完整的瘦素诱导的Ucp1表达。尽管瘦素激活了STZ诱导的糖尿病小鼠的BAT产热，但在Ucp1（-/-）小鼠中瘦素的抗糖尿病作用并未减弱。
这些结果表明，瘦素通过一种不需要副交感神经或交感神经支配的方式降低胰岛素缺乏型糖尿病中的血糖，因此意味着瘦素通过另一种中枢神经系统介导的机制或冗余的靶组织降低血糖。此外，我们得出结论，瘦素的降血糖作用独立于UCP1依赖性产热。
