Reimúndez, AlfonsoFernández-Peña, CarlosOrdás, PurificaciónHernández-Ortego, PabloGallego, RosalíaMorenilla-Palao, CruzNavarro, JuanMartín-Cora, FranciscoPardo-Vázquez, José L.Schwartz, Lindsay A.Arce, VíctorViana, FélixSeñarís, Rosa2023-01-162023-01-162022-10-17Reimúndez A, Fernández-Peña C, Ordás P, Hernández-Ortego P, Gallego R, Morenilla-Palao C, Navarro J, Martín-Cora F, Pardo-Vázquez JL, Schwarz LA, Arce V, Viana F, Señarís R. The cold-sensing ion channel TRPM8 regulates central and peripheral clockwork and the circadian oscillations of body temperature. Acta Physiol (Oxf). 2023 Mar;237(3):e13896.1748-1708http://hdl.handle.net/2183/32355[Abstract] Aim: 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 Tc.engCreative Commons Attribution-NonCommercial 4.0 International License (CC-BY-NC 4.0)http://creativecommons.org/licenses/by-nc/4.0/TRPM8Body temperatureCentral and peripheral clocksCircadian regulationSensory physiologyjournal articleopen access