Sa, Moonsun Yoo, Eun-Seon Koh, Wuhyun Park, Mingu Gordon Jang, Hyun-Jun Yang, Yong Ryoul Bhalla, Mridula Lee, Jae-Hun Lim, Jiwoon Won, Woojin Kwon, Jea Kwon, Joon-Ho Seong, Yejin Kim, Byungeun An, Heeyoung Lee, Seung Eun Park, Ki Duk Suh, Pann-Ghill Sohn, Jong-Woo Lee, C. Justin 2024-01-19T08:34:05Z 2024-01-19T08:34:05Z 2023-09-27 2023-09 2522-5812 https://pubs.kist.re.kr/handle/201004/113307 The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity. The authors identify a role for GABRA5 neurons in the lateral hypothalamus for energy balance regulation. Inhibiting these neurons increases weight gain and lipid accumulation through a process dependent on astrocytic GABA release. English Nature Publishing Group (Springer Nature) Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA Article 10.1038/s42255-023-00877-w 1 Nature Metabolism, v.5, no.9, pp.1506 - 1525 Nature Metabolism 5 9 1506 1525 N scie scopus 001062504200003 Endocrinology & Metabolism Endocrinology & Metabolism Article; Early Access REACTIVE ASTROCYTES GABAERGIC NEURONS ARCUATE NUCLEUS FOOD-INTAKE OREXIN WHITE ACTIVATION BROWN ADIPOSE-TISSUE MELANIN-CONCENTRATING HORMONE TONIC INHIBITION