Cold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue

Sep 26, 2017Biochimica et biophysica acta. Molecular cell research

Cold-sensing TRPM8 channel may influence daily rhythms in brown fat activity

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Abstract

TRPM8 channels are crucial for the temporal regulation of clock genes in brown adipose tissue, with significant findings related to energy metabolism.

TRPM8 transcripts showed temporal variation exclusively in brown adipose tissue (BAT).
Mice lacking TRPM8 lost the normal daily rhythm of the Per1 gene in their eyes during light-dark cycles.
These TRPM8 knockout mice exhibited a delay in locomotor activity in response to light compared to wild type mice.
Brown adipocytes from TRPM8 knockout mice displayed larger fat droplets than those from wild type or TRPV1 knockout mice.
Ucp1 and UCP1 protein levels were significantly lower in TRPM8 knockout mice compared to wild type mice.
In wild type mice, clock genes oscillated regularly, while TRPM8 knockout led to reduced expression and loss of oscillation in these genes.

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Transient receptor potential (TRP) channels are known to regulate energy metabolism, and TRPM8 has become an interesting player in this context. Here we demonstrate the role of the cold sensor TRPM8 in the regulation of clock gene and clock controlled genes in brown adipose tissue (BAT). We investigated TrpM8 temporal profile in the eyes, suprachiasmatic nucleus and BAT; only BAT showed temporal variation of TrpM8 transcripts. Eyes from mice lacking TRPM8 lost the temporal profile of Per1 in LD cycle. This alteration in the ocular circadian physiology may explain the delay in the onset of locomotor activity in response to light pulse, as compared to wild type animals (WT). Brown adipocytes from TrpM8 KO mice exhibited a larger multilocularity in comparison to WT or TrpV1 KO mice. In addition, Ucp1 and UCP1 expression was significantly reduced in TrpM8 KO mice in comparison to WT mice. Regarding circadian components, the expression of Per1, Per2, Bmal1, Pparα, and Pparβ oscillated in WT mice kept in LD, whereas in the absence of TRPM8 the expression of clock genes was reduced in amplitude and lack temporal oscillation. Thus, our results reveal new roles for TRPM8 channel: it participates in the regulation of clock and clock-controlled genes in the eyes and BAT, and in BAT thermogenesis. Since disruption of the clock machinery has been associated with many metabolic disorders, the pharmacological modulation of TRPM8 channel may become a promising therapeutic target to counterbalance weight gain, through increased thermogenesis, energy expenditure, and clock gene activation.

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Cold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue

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