RII β ‐PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning

Abstract The RII β subunit of cAMP‐dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RII β ‐knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RII β reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RII β ‐PKA in these neurons governs WAT browning are unknown. Here, this work reports that RII β ‐KO mice exhibit a robust WAT browning. RII β reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single‐cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RII β ‐KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RII β ‐PKA in DMH GABAergic neurons regulates WAT browning. Targeting RII β ‐PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.