Figure 3.

Diversity in stimulus sensing, fuel sources, and thermogenic mechanisms of brown and beige adipocytes. Thermogenic adipocytes receive signals from the sympathetic nerve terminals, including catecholamines, ATP, and adenosine. Together with secondary bile acid (2° BA), atrial/brain natriuretic peptide, thyroid hormone, and others not shown, adrenergic and purinergic signaling stimulates lipolysis that generates free fatty acids (FFAs) for mitochondrial fuel and UCP1 activation, promotes thermogenic gene expression, and initiates the futile calcium cycle in the endoplasmic reticulum. FFA and triacylglycerol-rich lipoproteins are taken up into adipocytes by CD36. Glucose can be stored as glycogen, undergo glycolysis, enter the hexosamine biosynthetic pathway for protein O-GlcNAcylation, be used for de novo lipogenesis, or fuel the thermogenic program. Activated BAT also clears BCAAs from the circulation and utilizes them in the mitochondria for thermogenesis via solute carrier family 25 member 44 (SLC25A44)-mediated transportation and branched-chain α-keto acid dehydrogenase (BCKDH)-dependent catabolism. Succinate is accumulated in activated BAT mitochondria to drive UCP1-dependent thermogenesis via reactive oxygen species and protein succinylation. The creatine futile cycle mediated by the creatine kinase (CK) triggers mitochondrial ATP turnover and UCP1-independent thermogenesis. N-Acyl amino acid is proposed to engage members of the SLC25 family, such as adenine nucleotide translocase (ANT) to uncouple mitochondrial respiration. A_2AR, adenosine A2A receptor; AR, adrenergic receptor; Epi, epinephrine; ETC, electron transport chain; F6P, fructose-6-phosphate; G6P, glucose-6-phosphate; Gpbar1; GLUT, glucose transporter; HSL, hormone-sensitive lipase; NE, norepinephrine; NPRA, natriuretic peptide receptor A; P2X, P2X receptor; PKA, protein kinase A; PKG, protein kinase G; RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SNS, sympathetic nerve system; TCA, the citrate cycle; TGR5, G-protein-coupled bile acid receptor; TR, thyroid hormone receptor; TZDs, thiazolidinediones; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.