Alternative Receptor Signaling for the Selective and Multifaceted Regulation of Human Brown Adipocytes

Brown adipose tissue (BAT) is increasingly recognized as a metabolically active organ in adult humans that contributes to systemic energy homeostasis and represents a potential therapeutic target for obesity-associated metabolic diseases. However, effective strategies to increase BAT mass or thermogenic activity in humans have not yet been established. Although β-adrenergic receptors have traditionally been viewed as the principal drivers of adaptive thermogenesis and adipocyte browning, β-adrenergic stimulation alone may be insufficient to safely enhance BAT thermogenic capacity due to systemic adverse effects. Emerging evidence suggests that alternative receptor-mediated signaling pathways contribute to the regulation of brown adipocyte function, including both UCP1-dependent and UCP1-independent thermogenic mechanisms, and systemic metabolic homeostasis. These pathways include G protein-coupled receptors, receptor tyrosine kinases, and nuclear receptors, which enable brown adipocytes to integrate endocrine, immune, nutritional, and thermal cues. In this review, we discuss recently characterized non-adrenergic receptor signaling pathways and their potential roles in regulating adipocyte browning and thermogenic activity in human adipose tissues. This review highlights the concept of selective modulation of non-adrenergic receptor signaling as a strategy to enhance adipocyte browning and thermogenic capacity while minimizing systemic adverse effects. Understanding these integrated signaling networks may facilitate the development of safer and more selective therapeutic strategies targeting brown adipocyte function in metabolic disease.