Dissecting sugar-induced modulation of gut-brain circuits | American Diabetes Association

Lisa Beutler, MD, PhD

Institution: Northwestern University Medical School, Chicago, Illinois
Project Title: Dissecting sugar-induced modulation of gut-brain circuits
Type of Grant:
Therapeutic Goal: Manage Diabetes
Diabetes Type: Obesity
Project Start Date: December 31, 2022
Project End Date: December 30, 2027
Focus: Integrated Physiology, Integrated Physiology\GLP-1, GIP, and Other Gut Hormones, Integrated Physiology\Regulation of Food Intake, Obesity, Obesity\Animal Models
Status: Active


Research Description

Sugary beverages are a major contributor to the diabetes and obesity epidemics, but the mechanisms underlying this connection remain poorly understood. Rapid communication between the gut and the brain about recently consumed nutrients is critical for maintaining energy and glucose balance. However, despite its clear link to metabolic disease, very little is known about how a high-sugar diet alters the dynamics of this communication. Specifically, it is unknown how chronically over-consuming sugar versus fat changes neural responses to food intake and satiation signals in ways that might promote the development of obesity and diabetes. Understanding how diet changes neural dynamics is critical for developing novel approaches to prevent and treat these diseases. Neuromodulatory therapies that harness the ability of the nervous system to control appetite and blood glucose hold tremendous promise in this arena, and not knowing which neural populations to target and how to modulate them remain a major barrier to their implementation. This project seeks to change that. The Beutler lab will monitor the activity of several neural populations critical for normal feeding and glucose balance in mice before and after a high-sugar diet. They will also use cutting-edge genetic tools to manipulate genetically defined groups of neurons and determine whether this rescues the adverse behavioral and metabolic effects of a high-sugar diet. These experiments will enhance understanding of how nutrition impacts brain function, determine how this goes awry during the development of obesity and diabetes, and identify neural targets for preventing and treating these diseases.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

Excessive sugar intake is clearly linked with the development of diabetes and obesity, but the mechanisms underlying this association is incompletely understood. This project aims to determine how excessive sugar intake disrupts gut-brain communication and alters neural responses to nutrients in ways that promote the development of these metabolic diseases. It will additionally address whether manipulating the activity of neural populations disrupted by sugar overconsumption can counteract the adverse metabolic effects of a high sugar diet. By dissecting in unprecedented detail how diet composition alters the function of the neural circuits that regulate body weight and blood glucose, this work will reveal novel approaches to treat and prevent diabetes and obesity.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

I want to understand how what we eat alters the activity of brain centers that control appetite and blood glucose at single-cell resolution, and how certain diets can promote the development of diabetes and obesity by disrupting neural activity. In the future, my lab will harness this knowledge to develop and test novel neural circuit-based therapies in rodent models of these diseases. Our ultimate goal is to see our discoveries translated into the clinic.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

As a clinical endocrinologist, I treat patients with diabetes and obesity every week. It is an exciting time in this field with rapidly improving treatment options finally available to patients. But there is much we still do not understand about the development and progression of these diseases, and unraveling these mechanisms has the potential to transform therapy and even lead to a cure for them. This is what motivates my research program. The ADA Pathway to Stop Diabetes Award will transform my research efforts, enabling my lab to invest in the most cutting-edge neuroscience tools in order to understand how diet promotes metabolic disease by altering neural activity. The goal of this work is to identify and test novel approaches to treat diabetes and obesity.

In what direction do you see the future of diabetes research going?

Advances in technology have enabled the generation of incredibly large and complex neuroscience datasets. This includes the type of single cell resolution neural recording data we will collect as part of this project. A major challenge for the future will be to understand what these data are telling us and how to translate this understanding into treatments for diseases that affect brain function, including diabetes and obesity. This will require collaboration across the fields of neuroscience, endocrinology, computer science, and engineering. As a physician-scientist it is my goal to lead interdisciplinary groups to pioneer circuit-based therapies for metabolic diseases.