Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism
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 pertu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/10/10/385 |
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| author | Kimberley D. Bruce Evgenia Dobrinskikh Hong Wang Ivan Rudenko Hong Gao Andrew E. Libby Sachi Gorkhali Tian Yu Andrea Zsombok Robert H. Eckel |
| author_facet | Kimberley D. Bruce Evgenia Dobrinskikh Hong Wang Ivan Rudenko Hong Gao Andrew E. Libby Sachi Gorkhali Tian Yu Andrea Zsombok Robert H. Eckel |
| author_sort | Kimberley D. Bruce |
| collection | DOAJ |
| description | 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 (NEXCreLPL<sup>flox</sup> (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPL<sup>flox</sup>). 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 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. |
| first_indexed | 2024-03-10T15:59:41Z |
| format | Article |
| id | doaj.art-55aab51c1667499598d86d4a9735ec5f |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T15:59:41Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-55aab51c1667499598d86d4a9735ec5f2023-11-20T15:22:40ZengMDPI AGMetabolites2218-19892020-09-01101038510.3390/metabo10100385Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic MetabolismKimberley D. Bruce0Evgenia Dobrinskikh1Hong Wang2Ivan Rudenko3Hong Gao4Andrew E. Libby5Sachi Gorkhali6Tian Yu7Andrea Zsombok8Robert H. Eckel9Division of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USADepartment of Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO 80045, USADivision of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USADivision of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USADepartment of Physiology, School of Medicine, Tulane University, New Orleans, LA 70112, USADepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USADivision of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USADivision of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USADepartment of Physiology, School of Medicine, Tulane University, New Orleans, LA 70112, USADivision of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USAThe 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 (NEXCreLPL<sup>flox</sup> (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPL<sup>flox</sup>). 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 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.https://www.mdpi.com/2218-1989/10/10/385lipoprotein lipaseneuronal metabolismfatty liverbrain-liver axisFLIM |
| spellingShingle | Kimberley D. Bruce Evgenia Dobrinskikh Hong Wang Ivan Rudenko Hong Gao Andrew E. Libby Sachi Gorkhali Tian Yu Andrea Zsombok Robert H. Eckel Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism Metabolites lipoprotein lipase neuronal metabolism fatty liver brain-liver axis FLIM |
| title | Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism |
| title_full | Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism |
| title_fullStr | Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism |
| title_full_unstemmed | Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism |
| title_short | Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism |
| title_sort | neuronal lipoprotein lipase deficiency alters neuronal function and hepatic metabolism |
| topic | lipoprotein lipase neuronal metabolism fatty liver brain-liver axis FLIM |
| url | https://www.mdpi.com/2218-1989/10/10/385 |
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