Mouse anti-Human MCHR1 monoclonal antibody, clone 4E8

In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect. In vitro validation of the modeling results revealed that three known modulators of melanin-concentrating hormone receptor 1 (MCHR1) show a previously unknown submicromolar affinity to the histamine H3 receptor (H3R). This synergistic activity may present a novel therapeutic option against obesity.

Ambient temperature (T-a) warming toward the high end of the thermoneutral zone (TNZ) preferentially increases rapid eye movement (REM) sleep over non-REM (NREM) sleep across species. The control and function of this temperature-induced REM sleep expression have remained unknown. Melanin-concentrating hormone (MCH) neurons play an important role in REM sleep control. We hypothesize that the MCH system may modulate REM sleep as a function of T-a. Here, we show that wild-type (WT) mice dynamically increased REM sleep durations specifically during warm T-a pulsing within the TNZ, compared to both the TNZ cool and baseline constant T-a conditions, without significantly affecting either wake or NREM sleep durations. However, genetically engineered MCH receptor-1 knockout (MCHR1-KO) mice showed no significant changes in REM sleep as a function of T-a, even with increased sleep pressure following a 4-h sleep deprivation. Using MCH-cre mice transduced with channelrhodopsin, we then optogenetically activated MCH neurons time locked with T-a warming, showing an increase in REM sleep expression beyond what T-a warming in yellow fluorescent protein (YFP) control mice achieved. Finally, in mice transduced with archaerho-dopsin-T, semi-chronic optogenetic MCH neuronal silencing during T-a warming completely blocked the increase in REM sleep seen in YFP controls. These data demonstrate a previously unknown role for the MCH system in the dynamic output expression of REM sleep during T-a manipulation. These findings are consistent with the energy allocation hypothesis of sleep function, suggesting that endotherms have evolved neural circuits to opportunistically express REM sleep when the need for thermoregulatory defense is minimized.