Hypothalamic astrocytes control systemic glucose metabolism and energy balance

The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neu-rons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism, and energy balance. This process recruits a mech-anism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Pos-itive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals, respectively, worsens or im-proves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.