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

Abstract

BACKGROUND AND PURPOSEMost 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 APPROACHWe 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. RESULTSCo-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 IMPLICATIONSOur 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. AbbreviationsAgRP, agouti-related peptide; ARC, arcuate nucleus; DIO, diet-induced obesity; DMH, dorsomedial hypothalamic nucleus; LepRb, the long form of leptin receptors; mCPP, meta-chlorophenylpiperazine; NPY, neuropeptide Y; NTS, nucleus of solitary tract; PMV, ventral premammillary nucleus; POMC, pro-opiomelanocortin; pSTAT3, phosphorylated STAT-3; VMH, ventromedial hypothalamic nucleus BJP British Journal of Pharmacology

Leptin applications in 2015

“…The combination of pramlintide/metreleptin, was one of the most promising ones, although the clinical trial was halted in 2011 due to undesirable laboratory findings [102]. Recent examples from animal studies indicate that drugs that activate the 5-hydroxytryptamine (5-HT)2C receptors, such as meta-chlorophenylpiperazine, could act as leptin sensitizers and can have additive body-weight lowering effects when co-administered with leptin in diet-induced obese mice [103*]. Furthermore, the administration of leptin along with insulin presents a synergistic effect on hypothalamic neurons to promote browning of the white adipose tissue and facilitate weight loss in mice [104*].…”

Critically Discuss the Revival of Leptin for Obesity Therapy

“…These leptin sensitisers target distinct neuroendocrine systems related to leptin signalling pathology. For instance, amylin and leptin, tri-infusion of cholecystokinin, leptin and amylin, and glucagon-like peptide 1 and leptin therapies are able to suppress food intake and enhance body weight loss than leptin monotherapy (Bhavsar et al, 1998;Roth et al, 2008;Trevaskis et al, 2008;Trevaskis et al, 2010;Yan et al, 2015). Alternatively, leptinrelated analogues which are capable of binding and activating the active leptin receptor OBR can be used to help solve some problems associated with natural leptin such as the issue of leptin being inactive, low stability and short half-life (Roujeau et al, 2014).…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…Another interesting interplay has been reported between the 5-HT 2CR and the leptin system. Co-administration of mCPP and leptin results in an additive reduction in body weight in diet-induced obese mice (Yan et al 2015). 5-HT2CR KO mice show leptin-independent hyperphagia and a diabetic phenotype 2008), whereas double leptin and 5-HT2CR KO mice show a synergistic disruption of glucose homeostasis and a profound diabetes phenotype .…”