Fig. 6

Key genes and signaling pathways involved in the brown fat activation and white fat browning. In response to cold, norepinephrine (NE) is released by the sympathetic nervous system and binds to the β3-adrenergic receptor (β3-AR) on the membrane of brown and beige adipocytes, which results in the activation of adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP) that activates protein kinase A (PKA). PKA phosphorylates and activates cAMP response element-binding protein (CREB) resulting in enhanced transcription of uncoupling protein-1 (UCP1) and PPAR-γ co-activator (PGC-1α). Activated PGC1-α also stimulates the expression of fibronectin type III domain-containing protein 5 (FNDC5) which encodes a type I membrane protein that is cleaved to form a newly identified hormone, irisin. Irisin works on white adipocyte to stimulate UCP1 expression. Another factor, positive regulatory domain containing 16 (PRDM16), forms a transcriptional complex with CCAAT enhancer-binding protein (C/EBP)-β and induces the expression of PPAR-γ and PGC1-α. In addition, the activation of PKA enhances the phosphorylation of hormone-sensitive lipase (HSL) and promotes the decomposition of triacylglycerol (TG) in lipid droplets into glycerol and fatty acids (FA) that enter the mitochondria for β-oxidation. Activated BAT replenishes these stores via the uptake of TG-derived FA, generated by lipoprotein lipase (LPL)-mediated hydrolysis of TG