Reimúndez Dubra, AlfonsoFernández Peña, CarlosOrdás, PurificaciónHernández Ortego, PabloGallego Gómez, María RosalíaMorenilla Palao, CruzNavarro, JuanMartín Cora, FranciscoPardo Vázquez, José LuisSchwarz, Lindsay A.Arce Vázquez, Víctor ManuelViana, FélixSeñarís Rodríguez, Rosa María2023-06-162023-06-162022Reimúndez, A, Fernández-Peña, C, Ordás, P, et al. The cold-sensing ion channel TRPM8 regulates central and peripheral clockwork and the circadian oscillations of body temperature. Acta Physiol. 2023; 237:e13896. doi: 10.1111/apha.138961748-1708http://hdl.handle.net/10347/30696Aim Physiological functions in mammals show circadian oscillations, synchronized by daily cycles of light and temperature. Central and peripheral clocks participate in this regulation. Since the ion channel TRPM8 is a critical cold sensor, we investigated its role in circadian function. Methods We used TRPM8 reporter mouse lines and TRPM8-deficient mice. mRNA levels were determined by in situ hybridization or RT-qPCR and protein levels by immunofluorescence. A telemetry system was used to measure core body temperature (Tc). Results TRPM8 is expressed in the retina, specifically in cholinergic amacrine interneurons and in a subset of melanopsin-positive ganglion cells which project to the central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. TRPM8-positive fibres were also found innervating choroid and ciliary body vasculature, with a putative function in intraocular temperature, as shown in TRPM8-deficient mice. Interestingly, Trpm8−/− animals displayed increased expression of the clock gene Per2 and vasopressin (AVP) in the SCN, suggesting a regulatory role of TRPM8 on the central oscillator. Since SCN AVP neurons control body temperature, we studied Tc in driven and free-running conditions. TRPM8-deficiency increased the amplitude of Tc oscillations and, under dim constant light, induced a greater phase delay and instability of Tc rhythmicity. Finally, TRPM8-positive fibres innervate peripheral organs, like liver and white adipose tissue. Notably, Trpm8−/− mice displayed a dysregulated expression of Per2 mRNA in these metabolic tissues. Conclusion Our findings support a function of TRPM8 as a temperature sensor involved in the regulation of central and peripheral clocks and the circadian control of Tceng© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposeshttp://creativecommons.org/licenses/by-nc/4.0/Body temperatureCentral and peripheral clocksCircadian regulationSensory physiologyTRPM8journal article10.1111/apha.138961748-1716open access