Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify 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 (DIO) mouse model. Gene-silencing of Gabra5 in LHA decreases weight gain, whereas chemogenetic inhibition of Gabra5LHA suppresses energy expenditure and increases weight gain. In DIO mouse model, Gabra5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Administration of a MAOB inhibitor, KDS2010 reduces weight gain significantly without affecting food intake, which is recapitulated by gene-silencing of astrocytic MAOB in LHA. We propose that firing of Gabra5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.