Deconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice

The role of non-neuronal glial cells in the regulation of adipose sympathetic nerve activity and adipocyte functions such as white adipose tissue lipid lipolysis is poorly understood. Here, we combine chemo/optogenetic manipulations of medio-basal hypothalamic astrocytes, real-time fiber photometry monitoring of white adipose tissue norepinephrine (NE) contents and nerve activities, electrophysiological recordings of local sympathetic inputs to inguinal white adipose tissue (iWAT), and adipose tissue lipid lipolytic assays to define the functional roles of hypothalamic astrocytes in the regulation of iWAT sympathetic outflow and lipolysis. Our results show that astrocyte stimulation elevates iWAT NE contents, excites sympathetic neural inputs and promotes lipolysis. Mechanistically, we find that sympathetic paravertebral ganglia (PG) partake in those astrocyte effects. We also find that astrocyte stimulation excites pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH), and chemogenetic inhibition of POMC neurons blunts the effects induced by astrocyte stimulation. While we cannot exclude potential roles played by other cell populations such as microglia, our findings in this study reveal a central astrocyte-peripheral adipocyte axis modulating sympathetic drive to adipose tissues and adipocyte functions, one that might serve as a target for therapeutic intervention in the treatment of obesity.