Brain circuits underlying the sympathetic control of the liver
Authors: Desmoulins Lucie , Molinas Adrien , Gao Hong , Davis Roslyn , Derbenev Andrei , Zsombok Andrea 
Published: May 2023

The sympathetic nervous system plays an important role in the maintenance of hepatic glucose homeostasis, through stimulating glucose production and glycogenolysis. Pre-sympathetic neurons in the brainstem and hypothalamus govern the sympathetic output to the liver and thus control hepatic metabolism and glycemia. Intriguingly, despite the importance of this central pathway, specific information regarding the neural circuits and properties of liver-related neurons is limited. In this study, we tested the hypothesis that liver-related neurons in the paraventricular nucleus of the hypothalamus (PVN) and ventral lateral medulla of the brainstem (VLM) are part of a pre-sympathetic central circuit that is involved in the control of energy intake and regulation of glucose homeostasis. First, liver-related neurons were identified with a retrograde trans-synaptic viral tracer and their phenotype was revealed. In the VLM, ~23.2% of liver-related neurons expressed Dopamine Beta Hydroxylase (n=5) and ~9.3% Tyrosine Hydroxylase (n=6), which is consistent with previous reports demonstrating that catecholaminergic neurons in the VLM play a critical role in glucose regulation. In the PVN, ~6.8% of liver-related neurons expressed oxytocin (n=7) and ~27.5% expressed Single Minded 1 (Sim1) protein (n=7), two major neuronal populations in the PVN known for their involvement in the regulation of energy metabolism. Next, pre-sympathetic liver-related PVN neurons with projections to the VLM were identified and optogenetic approach was used to reveal functional connections between PVN neurons and pre-sympathetic liver-related neurons in the VLM. Light stimulation of projections of Sim1-expressing PVN neurons resulted in evoked excitatory postsynaptic currents in a subset of liver-related VLM neurons, which suggests the existence of monosynaptic connections between PVN and pre-sympathetic liver-related neurons in the VLM. Then the involvement of pre-sympathetic, VLM-projecting PVN neurons was determined in the regulation of energy homeostasis using chemogenetic approaches. Stimulation of VLM-projecting PVN neurons increased blood glucose levels (basal=137± 6 mg/dl vs. CNO (1mg/kg)=181± 12 mg/dl; paired t-test P=0.01, n=9) and decreased food intake during refeeding (two way ANOVA on paired and repeated measures, P<0.0001, n=9), while the respiratory exchange ratio and locomotor activity were not altered. In summary, our data strongly suggest the existence of a central circuit involving direct connections between pre-sympathetic PVN and catecholaminergic, liver-related VLM neurons and demonstrate that these neurons are involved in the regulation of energy homeostasis. Moreover, these results provide novel information about the pre-sympathetic central circuits involved in the regulation of the liver, and thus energy homeostasis and are crucial for the development of new strategies to improve glucose homeostasis via the autonomic nervous system. NIDDK122842 and Tulane Brain Institute Marko Spark Innovation Research Fund 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.