Antagonism at the melanocortin 4 receptor by agouti related protein (AgRP) and α-MSH is a well-established downstream effector of leptin signaling, however, other factors, which feed into these pathways, may contribute to the cascade of events initiated by leptin. Of these, the serotonergic system has been implicated in the regulation of appetite and body weight [8
]. A supporting a role for 5HT2c receptors in energy metabolism was the finding that 5HT2c-R-KO mice are hyperphagic, obese and under specific dietary manipulations predisposed to diet-induced obesity [17
]. Furthermore, stimulation of the 5HT2c/1B receptor in rats resulted in decreased food intake and activation of neuronal activity in a manner similar to that induced by the anorectic drug D-fenfluramine, which was previously used to treat obesity [11
]. Thus, the question arises whether a significant crosstalk exists between the 5HT2c receptor pathway and the leptin pathway such that it would impact on the phenotypes of the LepTg mice.
Our findings that the LepTg mice are lean and almost fatless on a chow diet (13) but gain substantial amounts of fat when fed a high fat diet (HFD) (14) provides an experimental model to study the interaction of the 5HT2c receptor and leptin pathways. Thus, we investigated via a genetic strategy, the role of 5HT2c receptors in LepTg mice. Our findings that the LepTg/5HT2c-R-KO mice are similar in weight and adiposity to LepTg mice with intact 5HT2c receptors demonstrate that leptin has a greater effect on body weight than 5HT2c-R signaling.
Thus, 5HT2c receptors may not constitute a critical component of the overall leptin pathway with respect to body weight and adiposity. Rather, our data complement previous findings [17
] by strongly supporting the concept that the serotonergic system mediated by 5HT2c receptors regulates body weight and food intake via a neuronal circuitry different from that of leptin.
The cross between the LepTg and 5HT2c-R-KO mice followed by a HFD addressed the question whether these two predispositions to DIO [12
] would attenuate or exacerbate the DIO of either strain, thus defining the roles of their individual or combined pathways. Our findings indicate that these two predispositions synergistically interact to exacerbate DIO. Thus, the coupling of a hyperactive leptin pathway at the beginning of the HFD coupled with loss of 5HT2c-R function results in severe DIO. A corollary of this finding would suggest that presence of 5HT2c receptor signaling might actually attenuate DIO.
The nature of the mechanisms that underlie these differential effects on body weight and adiposity in LepTg mice with and without 5HT2c receptors was addressed by measuring the relative expression levels of the orexigenic neuropeptides NPY, AgRP and anorexigenic neuropeptides POMC and CART, which are respectively downregulated and upregulated by leptin [3
Our findings that the LepTg, 5HT2c-R-KO and LepTg/5HT2c-R-KO mice have relatively low and similar POMC levels suggest that perturbations in the 5HT2c-R and leptin pathways downregulate POMC expression to the same extent, precluding their differential phenotypes based on POMC expression alone.
Although, the elevated AgRP and NPY levels in LepTg and LepTg/5HT2c-R-KO but not 5HT2c-R-KO mice may account at least partly, for the shift of the leptin pathway from catabolic on the chow diet to anabolic on the high fat diet, their differential phenotypes is likely to be accounted for by the dysregulation of additional neuropathways regulating energy balance, such as leptin signaling defects [27
] in intra and extra hypothalamic brain regions [28
In summary, our findings demonstrate that during low fat feeding states, mechanisms downstream or independent of leptin signaling do not appear to require the presence of 5HT2c receptors as determined by the continuous lipodystrophy of LepTg/5HT2c-R-KO mice.
Conversely, the exacerbation of DIO inflicted upon HFD fed mice with two genetic susceptibilities to DIO indicates that the presence of 5HT2c receptors actually attenuates DIO, which may be caused at least in part by a disturbance in the relative ratios of POMC, AgRP and NPY levels. The extension of our findings suggest that although obesity treatment modalities aimed at 5HT2c receptors or the leptin/melanocortin pathway might be beneficial in DIO, a greater benefit could be derived from simultaneous pharmacological targeting of both pathways resulting possibly in synergistic therapeutic effects.