Zhou Ligang, Sutton Gregory M, Rochford Justin J, Semple Robert K, Lam Daniel D, Oksanen Laura J, Thornton-Jones Zoe D, Clifton Peter G, Yueh Chen-Yu, Evans Mark L, McCrimmon Rory J, Elmquist Joel K, Butler Andrew A, Heisler Lora K
Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
Cell Metab. 2007 Nov;6(5):398-405. doi: 10.1016/j.cmet.2007.10.008.
The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT(2C)R) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT(2C)R agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.
2型糖尿病及其相关的过早发病和死亡负担正在迅速增加，对新型有效治疗方法的需求迫在眉睫。我们在此报告，血清素2C受体（5-HT(2C)R）激动剂，通常因其厌食特性而被研究，在肥胖和2型糖尿病小鼠模型中显著改善葡萄糖耐量并降低血浆胰岛素水平。重要的是，5-HT(2C)R激动剂诱导的葡萄糖稳态改善发生在对摄食行为、能量消耗、运动活动、体重或脂肪量无影响的激动剂浓度下。我们确定，这种对葡萄糖稳态的主要作用需要黑皮质素-4受体（MC4Rs）的下游激活，但不需要MC3Rs。这些发现表明，对5-HT(2C)Rs进行药理学靶向可能独立于体重改变而增强葡萄糖耐量，并且这可能被证明是治疗2型糖尿病的一种有效且机制新颖的策略。
