Positive regulation by GABA_bR1 subunit of leptin expression through gene transactivation in adipocytes

Background: The view that γ-aminobutyric acid (GABA) plays a functional role in non-neuronal tissues, in addition to an inhibitory neurotransmitter role in the mammalian central nervous system, is prevailing, while little attention has been paid to GABAergic signaling machineries expressed by adipocytes to date. In this study, we attempted to demonstrate the possible functional expression of GABAergic signaling machineries by adipocytes. Methodology/Principal Findings: GABA_B receptor 1 (GABA_BR1) subunit was constitutively expressed by mouse embryonic fibroblasts differentiated into adipocytes and adipocytic 3T3-L1 cells in culture, as well as mouse white adipose tissue, with no responsiveness to GABA_BR ligands. However, no prominent expression was seen with mRNA for GABA_BR2 subunit required for heteromeric orchestration of the functional GABA_BR by any adipocytic cells and tissues. Leptin mRNA expression was significantly and selectively decreased in adipose tissue and embryonic fibroblasts, along with drastically reduced plasma leptin levels, in GABA_BR1-null mice than in wild-type mice. Knockdown by siRNA of GABA_BR1 subunit led to significant decreases in leptin promoter activity and leptin mRNA levels in 3T3-L1 cells. Conclusions/Significance: Our results indicate that GABA_BR1 subunit is constitutively expressed by adipocytes to primarily regulate leptin expression at the transcriptional level through a mechanism not relevant to the function as a partner of heterodimeric assembly to the functional GABA_BR.