Estrogen-Dependent Variation in the Contributions of TRPM4 and TRPM5 to Fat Taste

Sex differences in physiology have garnered significant interest of late; however, comparatively little is known about the effects of sex on the function of the peripheral taste system. Previously, we have shown that fat taste functions in a sexually dimorphic manner using molecular, cellular, and behavioral assays, and that a subtype of estrogen receptor (ER) proteins is highly expressed in Type II (receptor) cells. The underlying mechanisms of estrogen's action, though, remain unknown.

Here, we sought to better understand estrogen's role in fat taste transduction at the molecular level by initially focusing on the transient receptor potential channel types M4 (Trpm4) and M5 (Trpm5), which we have shown to play roles in estrogen-sensitive fatty acid signaling in taste cells.

Using a multidisciplinary approach, using Trpm5-deficient mice, electrophysiological and calcium imaging assays revealed that there are significantly reduced FA responses in both males and females in the estrus phase, whereas females in the proestrus phase did not show this, suggesting that there may be E2-dependent TRPM5-independent FA signaling in Type II cells. During periods of high levels of circulating estrogen, there was no significant difference in cellular responses to fatty acid (FA) stimuli between Trpm5^-/- mice and their wild-type counterparts. Moreover, supplemental estradiol enhanced linoleic acid (LA)-induced TRPM5-mediated taste cell activation. Finally, while Type II cells depend on TRPM4 and TRPM5 for FA taste cell activation, proestrus (high-estrogen) females showed a greater dependence on a TRPM5-independent pathway for fatty acid responsiveness.

Together, these results underscore the substantial regulatory role of estrogen in the taste system, particularly for fatty acid signaling. Given that the taste system guides food preferences and intake, these findings may have important implications for understanding sex-specific differences in diet and, ultimately, metabolic health.