Hypothalamic PVN astrocytes fail to properly set glutamate tone in obese mice contributing to impaired glucose metabolism in this condition

Abstract

The hypothalamus is key in the control of energy balance, but strategies targeting hypothalamic neurons 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 exacerbated Ca 2+ activity in hypothalamic paraventricular nucleus (PVN) astrocytes. Bidirectional chemogenetic manipulation of astrocyte Ca 2+ activity in lean mice stimulated or inhibited the activity of neighboring parvocellular neurons. Importantly, these effects translated into bidirectional regulation of sympathetic activity, glucose metabolism, and energy balance. We found that the astrocyte-mediated effects on PVN neurons were blocked by the glutamate receptor blocker kynurenic acid, and the astrocyte glutamate transport blocker TBOA, suggesting that the astrocyte-neuron signaling and the effects on glucose metabolism involved the astrocytic control of ambient glutamate levels. Notably, we found that TBOA alone stimulated neurons in lean mice but failed to evoke a response in obese mice. This suggests that the astrocyte glutamate transporter activity is impaired in obese mice. Finally, we found that chemogenetic inhibition of astrocyte Ca 2+ activity in obese mice improved glucose metabolism in this condition. Together, our results indicate that exacerbated astrocyte Ca 2+ activity leads to impaired glutamate transporter activity, standing as a likely mechanism contributing to altered PVN neuronal activity and glucose homeostasis during this condition. 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. NHLBI F32 HL158172 (MKK) NHLBI HL090948 (JES) NINDS NS094640 (JES) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.