Regulating how much to eat based on hunger levels is essential for animal survival. A deep brain region called the hypothalamus plays a central role in controlling these feeding behaviours.
By mapping the neural pathways in this region, researchers like Caroline Wee aim to identify appetite-regulating mechanisms that have stood the test of time across vertebrate evolution.
“We know that if something is important in biology, it will be very well-conserved through evolution,” explained Wee, a Principal Scientist at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB). “While the mouse hypothalamus is tiny relative to other brain regions, the fish hypothalamus occupies up to half of the brain, showing its importance in regulating basic functions.”
To compare the hypothalamic networks between fish and mouse models, Wee teamed up with A*STAR IMCB Principal Scientist Sarah Luo; Associate Director Wei Leong Chew at the A*STAR Genome Institute of Singapore (A*STAR GIS); Principal Scientist Anand Andiappan at the A*STAR Skin Research Labs (A*STAR SRL) and A*STAR Singapore Immunology Network (SIgN); and collaborators from Dartmouth University in the US. The study was funded by the A*STAR Brain-Body Initiative and the National Research Foundation Fellowship, and led by Vindhya Chaganty, a Scientist at A*STAR IMCB.
Using an advanced single-cell RNA sequencing technique called Act-seq, the researchers captured both the diversity and activity patterns of neurons in the zebrafish hypothalamus, focusing on the lateral hypothalamus, a region known to be involved in appetite control. They then used computational algorithms to align these zebrafish brain cell profiles with existing mouse hypothalamus datasets, revealing both shared and species-specific neuron types across these species.
This comparison revealed that many of the overlapping cell clusters were inhibitory neurons, highlighting their potential importance across evolution. Among them, one group stood out: neurons that express growth hormone (GH) receptors while also releasing tachykinin, a neurochemical linked to feeding behaviour. The team found that these neurons are most strongly activated during hunger-driven feeding frenzies. Moreover, brief exposure to human GH was sufficient to activate these neurons and boost food intake in otherwise satiated zebrafish.
Previously, ghrelin was the only identified hunger-promoting hormone. Now this study suggests that GH—typically known to regulate growth and metabolism over longer time scales of development—may also function as a fast-acting appetite signal, helping the body keep pace with changing energy demands.
“GH may be the new kid on the block for integrating metabolic needs with appetite control,” Wee said. “We are the first to identify an evolutionarily conserved hypothalamic cell type that could potentially mediate GH’s effects on appetite.”
Looking ahead, Wee and the team hope to better understand how and when this GH-responsive circuit contributes to hunger cues, as well as to identify the nutrients and biochemical interactions influencing its activity.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), A*STAR Genome Institute of Singapore (A*STAR GIS), A*STAR Singapore Immunology Network (SIgN) and A*STAR Skin Research Labs (A*STAR SRL).
