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

Br J Pharmacol. 2015 Jul;172(14):3510-21. doi: 10.1111/bph.13141. Epub 2015 May 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Diet / adverse effects*
  • Dose-Response Relationship, Drug
  • Leptin / administration & dosage
  • Leptin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / chemically induced
  • Obesity / etiology
  • Obesity / metabolism*
  • Phosphorylation / drug effects
  • Piperazines / administration & dosage
  • Piperazines / pharmacology*
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / administration & dosage
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Structure-Activity Relationship


  • 5-hydroxytryptamine2C receptor, mouse
  • Leptin
  • Piperazines
  • Receptor, Serotonin, 5-HT2C
  • STAT3 Transcription Factor
  • Serotonin 5-HT2 Receptor Agonists
  • Stat3 protein, mouse
  • 1-(3-chlorophenyl)piperazine