Immunometabolic benefits of sauna therapy through TRPV1

About This Grant

PROJECT SUMMARY Sauna therapy, also known as heat or hyperthermia therapy, is a non-invasive intervention traditionally used to improve a broad range of health outcomes, including pain relief, cardiovascular function, immune response, and insulin sensitivity. Emerging evidence suggests that its physiological benefits closely resemble those of aerobic exercise; however, the underlying molecular mechanisms remain poorly understood. This knowledge gap limits the clinical translation of sauna therapy, particularly for individuals with restricted mobility or exercise intolerance, such as the elderly and those with chronic conditions. The objective of this project is to elucidate the molecular pathways through which sauna therapy modulates metabolic and immune functions. We hypothesize that thermal activation of the transient receptor potential vanilloid 1 (TRPV1) channel—a heat-sensitive, non-selective calcium channel—reprograms cell-type-specific responses by enhancing intracellular calcium flux, thereby promoting thermogenic energy expenditure and anti-inflammatory macrophage polarization. Our preliminary studies demonstrate that repeated sauna exposure improves insulin sensitivity, prevents BAT whitening, and suppresses proinflammatory cytokine production—effects abolished in TRPV1 knockout mice. In vitro, heat adaptation increases TRPV1-mediated calcium influx in human brown adipocytes and promotes M2 macrophage polarization. These findings support a central role for TRPV1 in mediating heat-induced immunometabolic adaptations. In Aim 1, we will delineate the mechanisms by which heat adaptation enhances energy expenditure via brown thermogenesis. Using immortalized human brown adipocytes (hBA) and 3D brown adipose organoids (hBAO), we will investigate the interplay between TRPV1 activation, calcium cycling, Ca²⁺/ATPase activity, and both UCP1-dependent and -independent thermogenic pathways, along with effects on glucose/lipid metabolism and BAT-derived endocrine factors. In Aim 2, we will define the immunomodulatory role of sauna therapy in macrophage function. Using human peripheral blood mononuclear cells (PBMCs), we will assess TRPV1- mediated calcium signaling in M1/M2 polarization and efferocytosis. In parallel, we will use human white adipose organoids (hWAOs) to examine how heat adaptation reprograms adipose tissue macrophages (ATMs) during beige adipogenesis. These studies will uncover a novel TRPV1-dependent mechanism of heat-induced metabolic and immune remodeling in human adipose and immune cells. The successful completion of this project will provide a mechanistic foundation for sauna therapy as a scalable, accessible strategy to enhance metabolic health and immune resilience in vulnerable populations.