β3-Adrenergic Modulation of Adipose Tissue Metabolism

β3-Adrenergic receptors (β3-ARs) are G-protein-coupled receptors predominantly expressed on brown and beige adipocytes, where they transduce sympathetic stimuli into metabolic responses. Activation of β3-ARs elevates intracellular cyclic adenosine monophosphate (cAMP), triggering protein kinase A (PKA)–dependent phosphorylation cascades that culminate in lipolysis, mitochondrial biogenesis and induction of uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, promoting non-shivering thermogenesis and increased energy expenditure. In rodents, β3-AR agonism robustly induces browning of white adipose tissue (WAT), enhances substrate oxidation and improves systemic glucose homeostasis. In humans, β3-AR expression is lower and more variable, yet selective agonists can stimulate lipolysis and modest thermogenic responses, with emerging evidence for benefits in obesity, diabetes and cancer models. Beyond metabolic health, β3-AR–driven adipose remodelling influences sleep regulation, immune modulation and tumour-stroma interactions. Pharmacological modulation of β3-AR signalling thus holds promise as a multisystem intervention, with ongoing work to refine receptor selectivity, overcome catecholamine resistance and translate rodent findings into clinical applications.

Research from Nature Portfolio

Recent studies have demonstrated that clinically approved β3-AR agonists can extend benefits into oncology by promoting global browning of adipose depots. In animal cancer models, administration of a β3-AR agonist induced UCP1-dependent thermogenesis, suppressed tumour growth and reduced metastatic burden, revealing a novel host-mediated metabolic barrier to malignancy. Separately, selective activation of β3-ARs in mice increased non-rapid-eye-movement sleep via UCP1-dependent brown adipose mechanisms, an effect attenuated by genetic or chemical ablation of brown adipose tissue sensory innervation. These findings underscore the receptor’s role in integrating energy homeostasis with systemic physiology beyond classic metabolic endpoints.

β3-Adrenergic Modulation of Adipose Tissue Metabolism publication trend

The graph below shows the total number of articles in β3-adrenergic modulation of adipose tissue metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

β3-Adrenergic receptor (β3-AR): A G-protein-coupled receptor on adipocytes that mediates sympathetic lipolysis and thermogenesis.

Brown adipose tissue (BAT): A specialised fat depot rich in mitochondria and UCP1, responsible for non-shivering heat production.

White adipose tissue (WAT) browning: The process by which white fat acquires brown-like, thermogenic characteristics.

Uncoupling protein 1 (UCP1): A mitochondrial inner-membrane protein that dissipates the proton gradient to generate heat.

Non-shivering thermogenesis: Heat production by metabolic uncoupling in adipose tissue, independent of muscle activity.

Catecholamine resistance: A state in which adipocytes become less responsive to sympathetic neurotransmitters, reducing lipolysis.

Histone deacetylase 11 (HDAC11): An enzyme that removes acetyl groups from proteins, modulating gene expression and thermogenic pathways.

References

1. Mirabegron displays anticancer effects by globally browning adipose tissues. Nature Communications (2023).
2. Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues. Advanced Science (2024).
3. HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance. Journal of Clinical Investigation (2023).
4. β3-adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity. Journal of Clinical Investigation (2022).
5. The role of the brown adipose tissue in β3-adrenergic receptor activation-induced sleep, metabolic and feeding responses. Scientific Reports (2017).