Decreased inhibition of ventral brainstem liver-related neurons in high-fat diet fed mice

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Pre-sympathetic liver-related neurons in the ventrolateral and ventromedial medulla (VLM/VMM) participate in the regulation of hepatic carbohydrate and lipid metabolism. Increased sympathetic activity observed in diet-induced obese mice likely contributes to excessive hepatic glucose production, and thus to the development, and/or progression of type 2 diabetes mellitus. At the cellular level, change in neuronal activity and/or synaptic balance is one of the underlying mechanisms that can lead to increased sympathetic outflow. In this study, we tested the hypothesis that high-fat diet (HFD) diminishes glycinergic inhibition of liver-related neurons in the VLM/VMM. We crossed heterozygous glycine transporter 2 Cre (GlyT2Cre) mice with floxed channelrhodopsin 2 (ChR2-EYFP) mice to generate GlyT2-ChR2 expressing mice (GlyT2ChR2/EYFP). Liver-related neurons were identified in the VLM/VMM with a retrograde viral tracer and patch-clamp recordings were conducted. Whole-cell recordings from pre-sympathetic, liver-related neurons revealed that spontaneous inhibitory postsynaptic currents (sIPSCs) are mediated by GABA and glycine. Our data showed that increasing the activity of inhibitory inputs leads to increased glycine release. Next, light stimulation was used to trigger glycine release in GlyT2ChR2/EYFP mice. Light stimulation of ChR2-expressing glycinergic fibers triggered evoked IPSCs (eIPSCs) generated by co-release of GABA and glycine with identical time courses for the two neurotransmitters. Intriguingly, in HFD-fed mice we found that the amplitude of light evoked IPSCs was significantly decreased. These data suggest that liver-related neurons in the VLM/VMM are co-inhibited by GABA and glycine and in HFD-fed mice inhibition of liver-related neurons is reduced. This reduced inhibition of ventral brainstem neurons may contribute to increased sympathetic activity in diet-induced obesity. Supported by: NIDDK122842 and Tulane Brain Institute Marko Spark Innovation Research Fund. This is the full abstract presented at the American Physiology Summit 2024 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.