Brown and Beige adipocytes play a pivotal role in energy dissipation and metabolic homeostasis, and emerge as an attractive target for obesity and metabolic disease. Transient receptor potential (TRP) channels function as key sensory-metabolic transducers that integrate thermal, chemical, and dietary stimuli to modulate thermogenesis, adipocyte differentiation, mitochondrial activity, and sympathetic outflow. Several members of TRP channel family, including, TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM8, and TRPA1, influence adipose tissue plasticity however their role is variably understood. This review synthesizes current knowledge on TRP channels as nodal regulators of Ca-dependent signaling in brown and beige adipocytes, with a focus on AMPK/SIRT1 and PGC-1α pathways, mitochondrial remodeling, and neuro-adipose crosstalk. Dietary and natural TRP agonists such as capsaicin, menthol, cinnamaldehyde, and allyl isothiocyanate, consistently promote thermogenesis and metabolic benefits in preclinical models and emerging evidence suggests the potential for additive or cooperative metabolic effects when TRP agonists are combined with other therapeutic strategies, including incretin-based approaches; however, formal evidence of pharmacological synergy remains limited. Here, we critically review mechanistic insights linking TRP channel activation to thermogenic reprogramming, adipocyte differentiation, and CNS-adipose crosstalk. We further highlight the opportunities and challenges of leveraging TRP channels as polypharmacological targets in obesity therapeutics, with particular emphasis on natural agonists and combination therapies. This emerging field holds substantial promise, yet requires rigorous translational validation to establish safety, efficacy, and long-term metabolic benefits in humans. 2+
