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.

Abstract

The cAMP‐dependent protein kinase A (PKA) in GABAergic neurons in dorsal median hypothalamus (DMH) predominantly regulates white adipose browning. The enzymatic subtype‐conversion of PKA induced by RII β gene deficiency may be a crucial event for eliciting adipose browning. Targeting RII β‐PKA in DMH GABAergic neurons may offer a clinically useful way to promote adipose browning for treating obesity and metabolic disorders.