Williams Lab Provides New Insights into Treating Obesity

New research findings published in Science about a brain circuit that controls the feeling of fullness (satiation) could lead to targeted therapies for obesity or improve the effectiveness of currently available anti-obesity medications.

We asked Kevin Williams, Ph.D., an Associate Professor in the Center for Hypothalamic Research, to detail the work of the international team of collaborators.

Why is this research noteworthy?

This research reveals how GLP-1 receptor agonists, a type of anti-obesity medication, activate specific brain circuits to induce a sense of fullness before eating, providing new insights into treating obesity.

What are the top takeaways from the research?

1. GLP-1 receptor agonists increase the sense of fullness before eating, reducing food intake.
2. This effect is mediated by specific neurons in the hypothalamus that are activated before and during food consumption.
3. Understanding these mechanisms offers new targets for developing more effective treatments for obesity.

Does this build on previous findings from you or your lab, or other researchers at UTSW?

Yes – this study builds on previous findings by our lab published in 2019 and 2021 exploring the role of GLP-1 in regulating appetite and body weight.

Are there any distinctive tools, technology, training, grants, development initiatives or state or federal funding such as NIH that deserve mentioning?

Our work was supported by several grants, including those from the National Institutes of Health (NIH), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of General Medical Sciences (NIGMS). We used advanced techniques such as optogenetics, calcium imaging, and micro-endoscopy to study neural activity in the brain. 

How does this research advance the field?

This research advances the field by identifying specific brain circuits involved in pre-ingestive satiation, providing new targets for obesity treatments, and deepening our understanding of how anti-obesity drugs work.

1. Identifying Specific Neural Circuits: We discovered that GLP-1 receptor agonists specifically target neurons in the dorsomedial hypothalamus (DMH) to induce pre-ingestive satiation. The identification of a precise and novel brain circuit advances our understanding of the neural mechanisms underlying appetite control.
2. Demonstrating Pre-ingestive Satiation: Our research shows that the sense of fullness induced by GLP-1 receptor agonists occurs even before food intake, which is a novel finding. This pre-ingestive satiation mechanism offers a new perspective on how these drugs help reduce food consumption.
3. Identifying Primary GLP-1R Expressing Neurons: For the first time, we identified the primary GLP-1R expressing neurons that inhibit arcuate NPY/AgRP neurons. Stimulation of arcuate NPY/AgRP neurons motivates food-seeking and appetitive behavior, and it's notable that this circuit suppresses this activity. This discovery provides a new understanding of how GLP-1 receptor agonists work to suppress appetite.
4. Providing New Therapeutic Targets: By understanding the specific neurons and circuits involved, the field may be able to develop more targeted therapies for obesity that potentially have fewer side effects and are more effective in reducing food intake.

How does it tie into/advance toward clinical solutions for patients?

Uncovering the brain mechanisms through which GLP-1 receptor agonists induce feelings of fullness, may pave the way for developing more effective and targeted treatments for obesity, potentially leading to better clinical outcomes for patients struggling with weight management.

The insights from this study have several implications for advancing clinical solutions for obesity:

1. Enhanced Drug Efficacy: Understanding the specific brain circuits involved in pre-ingestive satiation allows for the development of more effective GLP-1 receptor agonists that can better target these pathways, potentially improving drug efficacy and patient outcomes.
2. Personalized Treatment Strategies: Our findings could lead to personalized treatment approaches based on individual neural responses to GLP-1 receptor agonists. This can help tailor treatments to patients’ specific physiological and neural profiles, enhancing treatment success.
3. New Therapeutic Avenues: By identifying new neural targets, this research opens up possibilities for developing novel therapies that specifically activate or modulate these brain circuits, offering new options for patients who may not respond well to current treatments.
4. Reducing Side Effects: Targeting specific brain circuits involved in satiation can help minimize side effects associated with broader-acting drugs, making treatments safer and more tolerable for patients.

Who was involved in the research?

This research was conducted collaboratively between my lab at UT Southwestern and investigators from Seoul National University in Korea. The work at UT Southwestern was led by Eunsang Hwang, Ph.D., who is a co-first author of the manuscript. Other contributors from UT Southwestern included Laurent Gautron, Ph.D., an Assistant Professor in the Center for Hypothalamic Research, and Williams Lab members Jason Ajwani, B.S., Kyle Grose, and Bryan Portillo, B.S.

 

To learn more about Dr. Williams' research, visit the Williams Lab site.