{"doi":"10.20944/preprints202009.0484.v1","title":"Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism","abstract":"The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here we show that despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox [LPL KD]) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to WT controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence Lifetime Imaging Microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of the free vs. bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in, or over-expressing, LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.","journal":"Preprints.org","year":2020,"id":122446,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":563637,"name":"Hong Wang","orcid":"0000-0001-7450-2984","position":1,"is_corresponding":false},{"id":451789,"name":"Evgenia Dobrinskikh","orcid":"0000-0003-4595-2913","position":2,"is_corresponding":false},{"id":452400,"name":"Ivan A. Rudenko","orcid":null,"position":3,"is_corresponding":false},{"id":563638,"name":"Hong Gao","orcid":"0000-0002-3050-6462","position":4,"is_corresponding":false},{"id":328129,"name":"Andrew E. Libby","orcid":"0000-0003-3726-2170","position":5,"is_corresponding":false},{"id":452401,"name":"Sachi Gorkhali","orcid":null,"position":6,"is_corresponding":false},{"id":451792,"name":"Tian Yu","orcid":"0000-0001-9279-3076","position":7,"is_corresponding":false},{"id":451793,"name":"Andrea Zsombok","orcid":"0000-0002-1412-0041","position":8,"is_corresponding":false},{"id":35944,"name":"Robert H. Eckel","orcid":"0000-0002-4870-4600","position":9,"is_corresponding":false},{"id":325810,"name":"Kimberley D. Bruce","orcid":"0000-0001-5656-1534","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:14:51.076430Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}