High-fat diet induced obesity decreases the inhibition of liver-related neurons in the mouse ventral brainstem

The rostral ventrolateral medulla (VLM) and ventromedial medulla (VMM) are important pre-sympathetic areas in the brainstem that control the activity of the sympathetic nervous system. Pre-sympathetic neurons of the VLM/VMM play a crucial role in regulating homeostatic functions including liver functions and metabolism. Indeed, high-fat diet (HFD) induced obese mice were shown to have increased sympathetic nerve activity. Despite that GABA and glycine were identified as two inhibitory neurotransmitters that regulate the activity of pre-sympathetic VLM/VMM neurons, very little is known about GABAergic and glycinergic inhibitory mechanisms controlling the activity of pre-sympathetic neurons in HFD fed mice. In this study, GlyT 2 ChR2/EYFP mice were generated by crossing glycine transporter 2 Cre (GlyT2 Cre ) mice with floxed channelrhodopsin 2 (ChR2 EYFP ) mice to test the hypothesis that obesity leads to altered inhibition of liver-related neurons in the VLM/VMM. We used PRV-614, a retrograde viral tracer, to identify liver-related neurons in the VLM/VMM and conducted patch-clamp recordings from labeled pre-sympathetic neurons. Our data showed that spontaneous inhibitory postsynaptic currents (sIPSCs) in liver-related VLM/VMM neurons are mediated by GABA and glycine. Light stimulation of GlyT 2 ChR2/EYFP expressing fibers triggered evoked IPSCs generated by co-release of GABA and glycine. In HFD fed mice, the amplitude of evoked IPSCs was significantly reduced compared with the amplitude of pre-sympathetic neurons in control diet fed mice. In HFD fed mice, slower kinetics of the light evoked IPSCs were found in liver-related VLM/VMM neurons. These findings suggest that GABA and glycine co-inhibit liver-related neurons in the VLM/VMM and the inhibition of pre-sympathetic liver-related neurons is reduced in HFD fed mice. This suppression of inhibition may contribute to increased sympathetic activity in diet-induced obesity. NIH DK122842 (to AZ and AVD) and DK137224 (to AVD and AZ) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.