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 wilt type (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 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.
Highlights
The liver is central to the pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease
We demonstrate that obese mice with neuronal lipoprotein lipase (LPL) deficiency show improved glucose tolerance with aging, involving reduced hepatic lipid accumulation and altered activity of liver-related neurons in the paraventricular nucleus (PVN)
Mechanisms related to neuronal inputs to the autonomic nervous system (ANS) control of hepatic metabolism remain unclear
Summary
The liver is central to the pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease. It is thought that hepatic lipid accumulation precedes insulin resistance [1,2], which plays a pivotal role in the development of T2DM [3]. Hepatic neutral lipid accumulation and the incidence of non-alcoholic fatty liver disease (NAFLD) increase markedly with age [4]. Preventing hepatic fat accumulation is a promising strategy to prevent age-associated metabolic disease. The autonomic nervous system (ANS) plays a key role in regulating hepatic metabolism [5] and is, an attractive target for the treatment of metabolic disease. Metabolic signals from the hypothalamus reach the liver via neuronal pathways that include the brain stem, the sympathetic nerves, and the vagus nerve. The metabolic characteristics of hypothalamic preautonomic neurons remain undefined
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