TLQP-21/C3aR1 does not possess lipolytic properties per se. TLQP-21 enhances β-AR-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of HSL. TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. TLQP-21 treatment decreases body weight and fat mass in DIO mice by a mechanism involving β-AR and C3aR activation. TLQP-21 anti-obesity effect is not associated with adverse metabolic effects.