TY - JOUR
T1 - Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice
AU - Yan, Chunling
AU - Yang, Yongjie
AU - Saito, Kenji
AU - Xu, Pingwen
AU - Wang, Chunmei
AU - Hinton, Antentor Othrell
AU - Yan, Xiaofeng
AU - Wu, Qi
AU - Tong, Qingchun
AU - Elmquist, Joel K.
AU - Fukuda, Makoto
AU - Xu, Yong
N1 - Publisher Copyright:
© 2015 The British Pharmacological Society.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Background and Purpose 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. Experimental Approach 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. Results 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. Conclusions and Implications 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.
AB - Background and Purpose 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. Experimental Approach 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. Results 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. Conclusions and Implications 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.
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U2 - 10.1111/bph.13141
DO - 10.1111/bph.13141
M3 - Article
C2 - 25817043
AN - SCOPUS:84933052892
SN - 0007-1188
VL - 172
SP - 3510
EP - 3521
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 14
ER -