# Brain Circuits Involved in the Sympathetic Control of the Liver

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $585,290

## Abstract

The autonomic nervous system plays a significant role in the regulation of hepatic metabolism.
Activation of hepatic sympathetic nerves increases hepatic glucose production (HGP) and glycogenolysis, and
increased HGP largely contributes to the pathogenesis of type 2 diabetes mellitus. Therefore, without a full
understanding of the neural circuits involved in the regulation of the liver, there is a barrier to develop
strategies to control glucose levels via the brain-liver pathway. The overall long-term goal of this proposal is to
elucidate the fundamental relationship between central autonomic control and hepatic carbohydrate
metabolism. The paraventricular nucleus (PVN) of the hypothalamus is a critical command center controlling
autonomic outflow and, thereby, influencing glucose and energy homeostasis. Since impaired glucose
homeostasis in diabetic patients involves central circuits controlling autonomic output, the immediate objective
of this proposal is to investigate the contribution of pre-sympathetic, liver-related PVN and ventral brainstem
neurons to the maintenance of HGP and insulin action using in vivo and in vitro approaches. Our preliminary
observations from diet-induced obese (DIO) mice demonstrate an overall shift toward excitation in liver-related
PVN neurons and a diminished suppression of excitatory neurotransmission by insulin in pre-sympathetic
ventral brainstem projecting PVN neurons. Furthermore, our data also show that liver-related brainstem
neurons receive excitatory inputs from PVN neurons. These observations lead to the central hypothesis that
monosynaptic connections between pre-sympathetic, liver-related PVN and ventral brainstem neurons are
necessary for the regulation of hepatic carbohydrate metabolism. The proposed studies will define
hypothalamic and ventral brainstem circuits involved in the sympathetic control of the liver using retrograde
viral tracing and circuit mapping in combination with immunostaining. The electrophysiological studies will
determine the cellular properties of liver-related neurons in control and DIO mice. Functional connections
between PVN and liver-related ventral brainstem neurons will be revealed with optogenetics. The proposed in
vivo studies will determine the contribution of liver-related neurons to hepatic glucose production and insulin
action. Pharmacogenetic stimulation and inhibition of neurons will be used in combination with
hyperinsulinemic-euglycemic clamp studies in conscious intact and adrenalectomized mice. Sympathetic
activity will be assessed in a variety of organs and tissues. The outcomes of the proposed studies will establish
the contribution of hypothalamic and ventral brainstem circuits to hepatic carbohydrate metabolism, advance
our knowledge of sympathetic control of the liver, and may provide new strategies for the improvement of
glycemic status in diabetic patients via autonomic control.

## Key facts

- **NIH application ID:** 9998513
- **Project number:** 1R01DK122842-01A1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Andrei Derbenev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,290
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998513

## Citation

> US National Institutes of Health, RePORTER application 9998513, Brain Circuits Involved in the Sympathetic Control of the Liver (1R01DK122842-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998513. Licensed CC0.

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