How GABA neurones in the DVC control glucose metabolism

Summary

The Dorsal Vagal Complex (DVC) of the brain is an important regulator of glucose metabolism and food intake. The Nucleus of the Solitary Tract (NTS) in the DVC senses insulin and triggers a neuronal relay to decrease hepatic glucose production (HPG) in rodents. Recently we discovered that insulin inhibits GABA neurones in the NTS to control HGP. We aim to investigate how inhibition of GABA neurones can affect the communication between the DVC and the liver.

Overnutrition leads to the central nervous system losing the ability to sense changes in hormonal levels and to maintain the whole-body energy balance. Interestingly, in high-fat diet (HFD)-fed rodents, the DVC becomes insulin resistant and loses the ability to regulate HGP. We aim to investigate how HFD affects the ability of GABA neurones to respond to insulin.

Aim 1: Understand how GABA neurones in the DVC can regulate HPG.

• We will first analyse how insulin affects the activity of GABA neurones using 2-photon calcium imaging (the second supervisor is an expert of this technique and already produced interesting preliminary data). To identify the network of neurones that is involved in the regulation of glucose metabolism, we will perform retrograde neuronal tracing to highlight which neurones in the DVC projects to the liver. We will then perform 2-photon calcium imaging to understand how GABA neurones modulate the activity of the liver-projecting neurones. This will be the first complete characterization of the neuronal network in the DVC responsible for controlling blood glucose levels.

Aim 2: Understand the molecular changes associated with HFD-feeding and obesity that occur in GAB neurones in the DVC.

• Using translating ribosome affinity purification (TRAP) sequencing (TRAP-seq) (technique well established in our laboratory), we will measure changes in translating mRNA in GABA neurones of the DVC of insulin resistant and obese rats. With this technique we will identify through next generation sequencing how HFD-feeding affects GABA neurones at the molecular level. We will then use this knowledge to develop a molecular approach that can restore ability of GABA neurones to modulate the liver-projecting neurones. This experimental approach has the potential to identify novel target molecules that could be used to design drugs that can prevent the development of insulin resistance in the brain.

References

• Patel, B., New, L., Griffiths, J. C., Deuchars, J., & Filippi, B. M.: Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain. Molecular Metabolism, 2020, 43, 101123
• Filippi B.M., Abraham M. A., Silva P. A., Rasti M., LaPierre M. P., Bauer P. V., Rocheleau J. V., & Lam T. K. T.: Dynamin-related protein 1-dependent mitochondrial fission changes in the dorsal vagal complex regulate insulin action. Cell Reports. 2017 March 7; 18, 2301–2309
• Haigh, J. L., New, L. E., & Filippi, B. M.: Mitochondrial Dynamics in the Brain Are Associated With Feeding, Glucose Homeostasis, and Whole-Body Metabolism. Frontiers in Endocrinology, 2020 1–17. (Review)

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