Fig. 1. Signaling and acute activation of UCP1-dependent thermogenesis in brown adipocytes.

Left: norepinephrine (NE) released in response to physiological stimuli (e.g. cold exposure or overfeeding) activates a cAMP-dependent pathway leading to the release of fatty acids from cellular lipid stores. β₃, β₃-adrenergic receptor; G_s, G_αs protein; AC, adenylate cyclase; PKA, protein kinase A; HSL, hormone sensitive lipase. Right: free fatty acids interact to activate UCP1 in mitochondria, overcoming inhibition of the protein by cytosolic purine nucleotides. Activated UCP1 catalyses the leak of protons across the mitochondrial inner membrane, dissipating the electrochemical proton gradient generated by the respiratory chain that would otherwise drive ATP synthesis. As a result, the energy from the oxidation of respiratory substrates is released as heat.