Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Area of Science:

• Metabolic Health
• Adipose Tissue Biology
• Pharmacology

Background:

• Brown adipose tissue (BAT) thermogenesis is a key target for improving metabolic health.
• Previous research suggested beta-3 adrenergic receptors (β3-AR) mediate human BAT thermogenesis.
• Clinical trials targeting β3-AR for BAT stimulation have yielded poor results.

Purpose of the Study:

• To investigate the specific adrenergic receptor signaling pathways responsible for human BAT thermogenesis.
• To determine if β3-AR agonists can effectively stimulate BAT thermogenesis in humans.
• To identify the primary adrenergic receptor mediating BAT lipolysis and thermogenesis in humans.

Main Methods:

• Administration of a β3-AR agonist (mirabegron) at varying doses.
• Assessment of off-target binding to β1-AR and β2-AR.
• In vitro studies using human brown adipocytes involving β2-AR stimulation/inhibition and gene knockdown (ADRB1, ADRB2, ADRB3).

Main Results:

• Mirabegron only increased BAT thermogenesis at maximal doses, causing off-target effects.
• Off-target binding affected cardiovascular responses (β1-AR) and white adipose tissue lipolysis (β2-AR).
• Human brown adipocytes express ADRB2 alongside UCP1; β2-AR signaling mediates BAT lipolysis and thermogenesis.

Conclusions:

• Human BAT thermogenesis is primarily mediated by β2-AR signaling, not β3-AR.
• Targeting β3-AR is ineffective for stimulating human BAT thermogenesis due to off-target effects.
• β2-AR represents a more promising therapeutic target for modulating human BAT activity and metabolic health.