Yan Chunling, Yang Yongjie, Saito Kenji, Xu Pingwen, Wang Chunmei, Hinton Antentor Othrell, Yan Xiaofeng, Wu Qi, Tong Qingchun, Elmquist Joel K, Fukuda Makoto, Xu Yong
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Medical College, Qingdao University, Qingdao, China.
Br J Pharmacol. 2015 Jul;172(14):3510-21. doi: 10.1111/bph.13141. Epub 2015 May 11.
Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.
We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors.
Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions.
Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.
大多数人类肥胖形式的特征是瘦素敏感性受损，因此，抗肥胖瘦素疗法对这些瘦素抵抗的肥胖患者的效果甚微。因此，开发提高瘦素敏感性的策略在肥胖研究领域具有高度优先性。
我们首先研究了将瘦素与间氯苯哌嗪（mCPP，一种5-HT2C和5-HT1B受体激动剂）联合给药对瘦素抵抗饮食诱导肥胖（DIO）小鼠能量平衡的影响。我们进一步评估了在经mCPP预处理的DIO小鼠或基因缺失5-HT2C受体的小鼠的各个脑区中瘦素诱导的信号转导和转录激活因子3（pSTAT3）的磷酸化情况。
mCPP与瘦素联合给药对DIO小鼠体重减轻有相加作用。此外，DIO小鼠的mCPP预处理增强了弓状核、腹内侧下丘脑核和腹侧乳头前核中瘦素诱导的pSTAT3。最后，5-HT2C受体缺失显著减弱了这些相同下丘脑区域中瘦素诱导的pSTAT3。
我们的研究提供了证据，表明激活5-HT2C受体的药物可作为瘦素增敏剂，并可与瘦素联合使用，以在DIO小鼠中实现额外的体重减轻。
