Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice

Abstract

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity. The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.

Trpm8modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

“…On the other hand, cold exposure affected femoral and vertebral trabecular bone volume in male, irrespective of the genotype (Figure 6). As previously mentioned, Trpm8 allows the detection of environmental cooling [14,15,32] and it has also been implicated in BAT thermogenesis and thermoregulatory processes [1,20].…”

“…Early publications on Trpm8 had reported no differences in core temperature associated with its global deletion in mice [32]. However, recently, Reimúndez et al (2018)…”

“…Thermoregulatory processes involve both the regulation of heat loss and generation of heat (i.e. thermogenesis) [1]. Mammals require energy to generate and/or conserve heat when in temperatures below their thermoneutral zone, which in mice is 28-32°C [2].…”

“…Previously, Trpm8 was primarily described to work as a peripheral thermal sensor; however, there is evidence that this cold-sensing channel is also involved in thermoregulation by promoting heat conservation and energy homeostasis [1]. Indeed, Trpm8 is considered as a potential target in obesity due to its function in regulating energy metabolism [1,[16][17][18][19][20]. Trpm8 has been found to trigger non-shivering thermogenesis by BAT and the beiging of WAT in mice [20] and humans [18].…”

“…Trpm8 has been found to trigger non-shivering thermogenesis by BAT and the beiging of WAT in mice [20] and humans [18]. Moreover, Trpm8 knockout (Trpm8-KO) mice presented features such as hyperphagia and reduced fat oxidation when housed at 21°C, which seemed to promote the development of obesity [1].…”