A paraventricular hypothalamic control of social stress susceptibility by targeting brown adipose tissue β3 adrenoceptor

Adipose tissue disturbance underlies the pathogenesis of major depressive disorder (MDD); however, the underlying neural and molecular mechanisms remain elusive. Utilizing a social defeat stress mouse model of MDD, we identified a paraventricular hypothalamic (PVH) control of susceptibility to social stress via β3 adrenoceptor (β3AR) signaling in the brown adipose tissue (BAT). Susceptible mice exhibited a significantly elevated expression of BAT β3AR. Pharmacological activation of β3AR increased immobility time in the forced swim test in naïve mice, and decreased social interaction time in mice subjected to subthreshold defeat. Retrograde tracing revealed a polysynaptic neural connection from the PVH to BAT. Chemogenetic activation of this projection induced depressive-like behaviors in subthreshold defeat mice and dysregulated their expression of β3AR downstream molecules, interleukin-6. Together, these results established a functional role for BAT β3AR in regulating susceptibility to social stress, which was modulated by neural inputs originating in the PVH.