An important monoamine neurotransmitter is serotonin, also known as 5-hydroxytryptamine (5-HT). Serotonin regulates appetite and nutrition in a variety of animal species. Historically, a number of pharmaceuticals were marketed to control body weight by increasing serotonin levels in the central nervous system, but they were subsequently withdrawn due to a variety of severe adverse effects. This is likely owing to the diversity of serotonergic neurons involved in the regulation of numerous physiological functions. Consequently, a greater understanding of the diversity of serotonergic neurons and their mechanisms for regulating feeding and energy balance may be advantageous for the development of novel weight control drugs.
On January 19, 2022, Zepeng Yao and Kristin Scott of the University of California, Berkeley, published a paper in Neuron entitled "Serotonergic neurons translate taste detection into internal nutrient regulation". Using Drosophila melanogaster as a model organism, the researchers elucidated the regulation of energy homeostasis by two serotonergic neuron subtypes.
Similar to mammals, activation of serotonergic neurons in Drosophila inhibits feeding significantly. However, compared to the tens of thousands of serotonergic neurons in mammals, the Drosophila brain contains only about 90 serotonergic neurons, providing a simplified model for investigating the specific serotonin loops that modulate feeding and energy balance. A region of the Drosophila brain known as the subesophageal zone (SEZ) is crucial for the regulation of taste and nutrition. Therefore, the researchers focused on the serotonergic neurons in this region, specifically the SEL neuronal cluster.
Using in vivo calcium imaging, the researchers found that the SEL neuron cluster contains two distinct subtypes of serotonergic neurons. One is activated by sweet taste, called sugar-SELs, and the other is activated by bitter taste, called bitter-SELs.
Through a series of optogenetic, in vivo imaging and behavioral experiments, the researchers found that sugar-SELs promote the secretion of insulin and reduce sugar intake in Drosophila. This suggests that sugar-SELs may use sweet taste stimuli to predict sugar intake, promote insulin secretion and prevent sugar overconsumption. It is worth mentioning that the sensory stimulation of food also promotes the release of a small amount of insulin at the beginning of a meal in mammals (including humans). This is called the cephalic phase insulin response and occurs before the rise in blood glucose levels. Thus, this study suggests that cephalic phase insulin release may be an evolutionarily conserved mechanism and suggests that serotonergic neurons mediate this mechanism.
The researchers found that another group of serotonergic neurons, bitter-SELs, are not directly involved in the regulation of feeding. Surprisingly, they project to the enteric nervous system and facilitate the contraction of the Drosophila crop. The Drosophila crop is a place where food is stored. The researchers speculate that when bitter substances in the environment (mostly harmful or toxic compounds) prevent feeding, bitter-SELs may facilitate the use of food reserves in the crop to replenish energy in response to potential food shortages.
This study demonstrates that two subtypes of serotonergic neurons utilize taste stimuli to predict future nutrition and changes in body energy, as well as to pre-regulate endocrine and digestive tract functions to maintain energy homeostasis in the body. This increases our understanding of the neural loop mechanisms of anticipatory regulation.
In future studies, the researchers intend to further elucidate the structural and functional diversity of serotonergic neurons, such as whether SEM neuron clusters also contain various subtypes and whether they also regulate taste, nutrition, and energy balance. These studies will contribute to our knowledge of the intricate modulation of nutrition and energy balance by distinct serotonin circuits.