Brown Adipose Tissue: Molecular Mechanisms of Regulation, Physiological Functions, and Therapeutic Targets

FIGURE 1. The hierarchical molecular network governing adipocyte fate and browning. Adipocyte browning is governed by a multilayered molecular network. Core transcription factors (PPARγ, C/EBPβ, PRDM16, PGC‐1α) drive thermogenic differentiation, while epigenetic modifications (histone/DNA remodeling) modulate chromatin accessibility. Concurrently, microRNAs fine‐tune key signaling pathways. This hierarchical system ultimately dictates the balance between white fat storage and brown/beige energy dissipation.

FIGURE 2. Central and peripheral signaling pathways regulating thermogenesis in brown adipose tissue. Cold signals activate the hypothalamic–sympathetic neuroaxis, triggering norepinephrine release in BAT. β‐Adrenergic stimulation drives the cAMP–PKA cascade, inducing lipolysis and UCP1‐mediated thermogenesis. This core pathway is modulated by cGMP/PKG, AMPK, mTOR, and BMP/Smad signaling, while TRP channels and Wnt/Notch pathways regulate progenitor fate. This integrated system dynamically coordinates BAT thermogenesis in response to environmental cues.

FIGURE 3. Canonical UCP1‐dependent and alternative UCP1‐independent thermogenic mechanisms in brown adipocytes. Brown adipocytes generate heat via canonical UCP1‐dependent proton leakage, which uncouples oxidative phosphorylation. This is complemented by three ATP‐consuming futile cycles: creatine cycling, Ca2 + cycling via RyR/SERCA, and triglyceride–fatty acid cycling. These UCP1‐independent mechanisms provide alternative thermogenic routes, particularly relevant when UCP1 activity is limited or in beige adipocytes.

FIGURE 4. Systemic metabolic crosstalk mediated by BAT as an endocrine and signaling hub. Brown adipocytes generate heat via canonical UCP1‐dependent proton leakage, which uncouples oxidative phosphorylation. This is complemented by three ATP‐consuming futile cycles: creatine cycling, Ca2 + cycling via RyR/SERCA, and triglyceride–fatty acid cycling. These UCP1‐independent mechanisms provide alternative thermogenic routes, particularly relevant when UCP1 activity is limited or in beige adipocytes.

FIGURE 5. Multimodal imaging strategies for the in vivo assessment of BAT. BAT is assessed by multimodal imaging. PET (1 8F‐FDG, 1 8F‐FTHA) and SPECT (1 2 3I‐MIBG) measure metabolism and sympathetic activity; CT provides anatomical reference. MRI (fat‐fraction, perfusion) and infrared thermography offer radiation‐free functional assessment. Photoacoustic and xenon imaging add complementary readouts. AI‐based radiomics and deep learning further enhance automated BAT detection, quantification, and phenotyping.

FIGURE 6. The interplay between aging, NAD+ metabolism, and BAT homeostasis. Aging reduces NAD+ levels, impairing sirtuin activity and mitochondrial function, leading to BAT whitening and metabolic decline. Therapeutic interventions target two fronts: enhancing BAT recruitment (cold, exercise, capsaicin, β3‐agonists) and restoring NAD+ pools (NR/NMN, CD38/PARP inhibition). Combined strategies addressing both pathways may counteract aging‐related metabolic dysfunction.