Detouring adrenergic stimulation to induce adipose thermogenesis

Abstract

Harnessing the thermogenic, energy-expending capacity of adipocytes has the potential to combat metabolic disorders. Although β₃-adrenergic receptor agonists are the best-known activators of thermogenesis, they carry considerable cardiovascular risks. A new study demonstrates the ability of G protein-coupled receptor 3 to intrinsically drive adipose thermogenesis independent of β₃-adrenergic receptor signalling.

Fig. 1 |. An alternative paradigm for the activation of adipose thermogenesis.

A simplified figure depicting the key differences between canonical thermogenesis (part a) and G protein coupled receptor 3 (GPR3)-mediated intrinsic thermogenic programming (part b). a | Cold induces the release of noradrenaline (mediated by the sympathetic nervous system), which binds to β-adrenergic receptors to stimulate cAMP production, leading to upregulation of thermogenic genes via protein kinase A (PKA). b | The mechanism discovered by Sveidahl Johansen et al. demonstrates that a GPCR ligand is unnecessary. Rather, a hitherto unidentified lipolytic signal greatly increases the expression of GPR3, which promotes cAMP production via its intrinsic N-terminal activity. ADRB1–3, β-adrenergic receptors; UCP1: uncoupling protein 1.