Keywords

taste; estrogen; TRPM4; TRPM5; fatty acid; sex differences

Abstract

Dietary fat is a highly palatable, energy-dense nutrient whose oral detection powerfully shapes ingestion patterns and metabolic outcomes. Despite clear behavioral and physiological evidence that fat can evoke distinct taste signals, the cellular and molecular mechanisms underlying its transduction remain poorly understood. A critical gap exists in our understanding of the cell-type-specific molecular pathways and how these signals are modulated by hormonal status. This dissertation delineates estrogen-dependent plasticity in FA transduction within the peripheral taste system, revealing coordinated, sex and cell-type-specific modulation of these pathways. To understand the missing mechanisms, FA-evoked responses were compared in Type II cells from wild-type and Trpm5-/- mice of both sexes, stratified by estrous stage. These experiments confirmed that robust activation by long-chain FAs requires both TRPM4 and TRPM5, establishing these monovalent cation channels as core effectors of canonical fat taste transduction. However, the relative contributions of TRPM4- and TRPM5-mediated signaling shift with circulating estrogen. During low estrogen states, females rely heavily upon the Type II cells and their TRPM5-dependent pathway.  Meanwhile, high-estrogen states potentiate TRPM5 activity while simultaneously engaging alternative depolarizing pathways, producing phase-dependent sex differences in FA responsiveness. Further, we examined the FA pathway in Type III cells, a population previously underexplored in lipid taste. Electrophysiological and molecular analyses revealed that Type III cells employ a CD36- and calcium-dependent mechanism that is independent of TRPM channels. Estrogen exerted divergent, cell-type-specific effects, enhancing FA responsiveness in Type II cells while suppressing it in Type III cells, thereby reweighting the relative predominance of these cell populations under different estrogenic conditions. Collectively, these findings identify estrogen as a key regulator of peripheral fat taste signaling by linking hormonal status to gustatory signaling. This work provides a mechanistic framework for cell-type-specific sex- and cycle-dependent differences in fat perception and identifies plausible targets for interventions to mitigate obesity risk.

Completion Date

2026

Semester

Spring

Committee Chair

Timothy Gilbertson

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Science

Format

PDF

Document Type

Dissertation

Identifier

DP0053090

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