RIIβ-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning

The RII beta subunit of cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RII beta-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RII beta reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RII beta-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RII beta-KO mice exhibit a robust WAT browning. RII beta 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 beta-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 beta-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RII beta-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Automated summary

The RII beta subunit of cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RII beta-knockout mice show leanness and increased UCP1 in brown adipose tissue. RII beta reexpression in hypothalamic GABAergic neurons rescues the leanness. The authors investigate the role of RII beta-PKA in white adipose tissue (WAT) browning and find that RII beta-KO mice exhibit robust WAT browning. They also demonstrate that RII beta-PKA in dorsal median hypothalamic GABAergic neurons regulates WAT browning and affects body weight. Targeting RII beta-PKA in DMH GABAergic neurons may have therapeutic potential for obesity and metabolic disorders.