Adipose tissue thermogenic signaling pathways

Adipose tissue thermogenic signaling pathways encompass the complex molecular networks that regulate energy expenditure through non-shivering thermogenesis in brown and beige adipocytes [1, 6]. The primary pathway involves the activation of the beta-3 adrenergic receptor (ADRB3) by norepinephrine, which triggers a cAMP-mediated cascade leading to the activation of uncoupling protein 1 (UCP1) in the inner mitochondrial membrane [8, 11]. UCP1 dissipates the proton gradient to generate heat instead of ATP, a process crucial for metabolic homeostasis [4, 10]. Other significant pathways include signaling by fibroblast growth factor 21 (FGF21), bone morphogenetic protein 7 (BMP7), and thyroid hormones, as well as transcriptional regulation by PGC-1alpha and PRDM16 [7, 10]. Pharmacological targeting of these pathways, such as with ADRB3 agonists like mirabegron or PPAR-gamma activators, aims to treat obesity and type 2 diabetes by increasing systemic energy expenditure and improving insulin sensitivity [2, 5]. However, challenges include cardiovascular safety concerns and the limited volume of active brown fat in adult humans compared to preclinical models [2, 11].

Other names

Thermogenic programAdipose browning pathwaysNon-shivering thermogenesis signalingBAT activation pathwaysBeiging of white adipose tissue

Activation of beta-3 adrenergic receptors to increase cAMP and UCP1 expression; activation of PPAR-gamma to promote adipocyte differentiation and browning; stimulation of FGF21 receptors to enhance thermogenic gene expression; uncoupling of mitochondrial respiration from ATP synthesis via UCP1 [2, 4, 8].