Meta-Chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice

Authors: YAN, CHUNLIN - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); SAITO, KENJI - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); HINTON, ANTENTOR - Children'S Nutrition Research Center (CNRC); YAN, XIAOFENG - Children'S Nutrition Research Center (CNRC); WU, QI - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; ELMQUIST, JOEL - University Of Texas Southwestern Medical Center; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC); XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: British Journal of Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/22/2015
Publication Date: 7/1/2015
Citation: Yan, C., Yang, Y., Saito, K., Xu, P., Wang, C., Hinton, A.O., Yan, X., Wu, Q., Tong, Q., Elmquist, J.K., Fukuda, M., Xu, Y. 2015. Meta-Chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice. British Journal of Pharmacology. 172(14):3510-3521.

Interpretive Summary: Obese individuals are at an increased risk of developing type II diabetes, cardiovascular disease and cancer. Obesity is associated with 300,000 premature deaths every year. These figures highlight the urgent need to develop more effective therapies to combat the disease. Here we demonstrated that a combination of leptin (a hormone that helps prevent obesity) and meta-chlorophenylpiperazine (mCPP) can effectively reduce body weight in obese mice. These results provide pre-clinical evidence for this combined regimen to potentially treat human obesity.

Technical Abstract: 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.