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-HT<inf>2C</inf> and 5-HT<inf>1B</inf> 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-HT<inf>2C</inf> 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-HT<inf>2C</inf> receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. Conclusions and Implications Our study provides evidence that drugs, which activate 5-HT<inf>2C</inf> receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.
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