A new study from researchers at UHN has found that activating a protein called Takeda G protein-coupled receptor 5 (TGR5) in a specific brain region—the nucleus of the solitary tract (NTS)—can reduce food intake and improve signalling pathways disrupted in obesity.
Eating increases the levels of bile acid in the blood. Bile acids are made in the liver from cholesterol and undergo several chemical changes, eventually aiding fat digestion, regulating cholesterol levels, and signalling through specific receptors (like TGR5) that influence metabolism. Parts of the brainstem—such as the NTS, which processes signals from internal organs, and the area postrema (AP), which detects hormones related to hunger and nausea—help regulate appetite. However, it is unclear whether bile acids activate TGR5 in these brain regions to regulate feeding.
Obesity is often linked to leptin resistance, a condition where the hormone leptin no longer signals the brain effectively to suppress appetite. While leptin action in the NTS is known to affect food intake, the underlying pathways are poorly understood.
Using lab models, a research team led by Dr. Tony Lam investigated the relationship between TGR5 and leptin, examining whether activating the TGR5 receptor in the NTS or AP could influence appetite and leptin sensitivity.
In collaboration with Dr. Allison Xu from the University of California, San Francisco, they found that stimulating TGR5 in the NTS lowered food intake without causing nausea. Additionally, activating TGR5 in the NTS enhanced the brain’s sensitivity to leptin by boosting a key leptin-related signalling pathway (leptin-STAT3).
Findings also revealed that in these models, a high-fat diet interfered with natural signals to TGR5 in the NTS that normally help control appetite. When they directly added this signal back into the brain, it improved leptin signalling and reduced appetite.
Overall, this study indicates that TGR5 in the NTS plays a key role in regulating food intake by enhancing leptin signalling. TGR5 could be a promising target for treating obesity by combating leptin resistance.
Kyla Bruce, Doctoral Candidate at the Institute of Medical Science at the University of Toronto and UHN, is co-first author of the study.
Dr. Song-Yang Zhang, former Postdoctoral Researcher at UHN and current Assistant Professor at McGill University, is co-first author of the study
Dr. Tony Lam, Senior Scientist at Toronto General Hospital Research Institute and Professor in the Department of Physiology and Medicine at the University of Toronto, is the corresponding author of the study.
This work was supported by the Canadian Institutes of Health Research, the Banting and Best Diabetes Centre, the Government of Ontario, the Joseph and Vera Long Foundation, and UHN Foundation.
Dr. Tony Lam is a Tier 1 Canada Research Chair in Obesity
Bruce K, Zhang SY, Garrido AN, Wang MT, Bachor TP, Wang P, Xu AW, Yang Z, Lam TKT. Pharmacological and physiological activation of TGR5 in the NTS lowers food intake by enhancing leptin-STAT3 signaling. Nat Commun. 2025 May 29. doi: 10.1038/s41467-025-60331-1.