Immune and psychogenic fever arise through UCP1-independent thermogenic mechanisms

Brown adipose tissue (BAT) thermogenesis is essential for cold defense, but its contribution to fever and emotionally induced hyperthermia (psychogenic fever) remains disputed. Here we address this issue using genetic, surgical, physiological, and molecular approaches in rats. We generated UCP1 knockout rats, in which classical BAT thermogenesis is abolished, and examined body temperature responses to systemic inflammation induced by lipopolysaccharide and to emotional stressors such as restraint and cage exchange. Despite profound impairment of cold-induced and {beta}3-adrenergic-induced thermogenesis, UCP1 deletion did not affect LPS- or stress-evoked elevations in core or interscapular temperature. Surgical removal of interscapular BAT in wild-type rats likewise failed to alter these hyperthermic responses. Consistent with these findings, LPS and emotional stress induced only small, strain-dependent changes in the expression of thermogenic genes in BAT and minimally affected BAT mass, in marked contrast to the robust BAT activation elicited by {beta}3-adrenergic stimulation. Notably, emotional stress induced UCP3 expression in neck muscles, suggesting a potential contribution of skeletal muscle metabolic processes to stress-induced hyperthermia. Together, these findings demonstrate that both immune-induced and psychogenic fever occur independently of BAT thermogenesis and point to non-BAT tissues - likely including skeletal muscle - as candidate peripheral effectors supporting fever and emotional hyperthermia.