Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice
Chunling Yan1,2, Yongjie Yang1, Kenji Saito1
1Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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.
Insights
Activating 5-HT2C receptors with meta-chlorophenylpiperazine (mCPP) enhances leptin sensitivity. This combination therapy promotes additional weight loss in diet-induced obese (DIO) mice, offering a new strategy for obesity treatment.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Human obesity often involves leptin resistance, limiting the effectiveness of leptin therapy.
- Developing strategies to improve leptin sensitivity is crucial for obesity research.
Purpose of the Study:
- To investigate the effects of co-administering leptin with meta-chlorophenylpiperazine (mCPP) on energy balance in diet-induced obese (DIO) mice.
- To assess how mCPP affects leptin-induced STAT-3 phosphorylation (pSTAT3) in the brains of DIO mice, including those lacking 5-HT2C receptors.
Main Methods:
- DIO mice were treated with leptin and mCPP (a 5-HT2C/1B receptor agonist) to evaluate effects on body weight.
- Leptin-induced pSTAT3 in hypothalamic regions was measured in mCPP-pretreated DIO mice and in mice genetically deficient in 5-HT2C receptors.
Main Results:
- Co-administration of mCPP and leptin resulted in additive body weight reduction in DIO mice.
- mCPP pretreatment enhanced leptin-induced pSTAT3 in the arcuate, ventromedial hypothalamic, and ventral premammillary nuclei.
- The absence of 5-HT2C receptors significantly diminished leptin-induced pSTAT3 in these hypothalamic areas.
Conclusions:
- Drugs activating 5-HT2C receptors can act as leptin sensitizers.
- Combining 5-HT2C receptor agonists with leptin may offer an effective strategy for additional weight loss in diet-induced obesity.
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