Complex interplay of neuronal and hormonal gut-brain responses to essential amino acid deficit.
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| Title: | Complex interplay of neuronal and hormonal gut-brain responses to essential amino acid deficit. |
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| Authors: | Kim, Boram (AUTHOR), Lee, Seongju (AUTHOR), Bae, Hyeyeon (AUTHOR), Kim, Shinhye (AUTHOR), Won, Jong-Hoon (AUTHOR), Kim, Dongwoo (AUTHOR), Jung, Byungkwon (AUTHOR), Kanai, Makoto I. (AUTHOR), Yoon, Sung-Eun (AUTHOR), Oh, Yangkyun (AUTHOR), Lee, Won-Jae (AUTHOR), Suh, Greg S. B. (AUTHOR) |
| Source: | Science. 5/21/2026, Vol. 392 Issue 6800, p1-15. 15p. |
| Subjects: | Essential amino acids, Protein deficiency, Animal feeding behavior, Neuropeptides, Neuroendocrine cells, Deficiency diseases |
| Abstract: | A deficit in dietary protein elicits a nutrient-specific appetite, yet the underlying mechanisms remain poorly understood. In this work, we identify coordinated neuronal and systemic mechanisms in Drosophila that drive an essential amino acid (EAA)–specific appetite. EAA deprivation increases neuropeptide CNMamide (CNMa) expression in gut enterocytes, activating enteric neurons and ellipsoid body neurons in the brain to promote EAA intake through two complementary pathways: a rapid neuronal gut-brain axis and a slower hormonal route. CNMa suppresses the activity of sugar-sensing diuretic hormone 44 (DH44) neurons, thereby reducing carbohydrate intake and biasing feeding toward EAAs. Similarly, protein deprivation in mice promotes an EAA-specific appetite independently of fibroblast growth factor 21 (FGF21). Together, these findings reveal multilayered gut-brain mechanisms that regulate nutrient-specific feeding and maintain EAA homeostasis across species. Editor's summary: A lack of sufficient dietary proteins leads to nutrient-specific appetite for essential amino acid (EAA)- or protein-rich food. In Drosophila, the peptide CNMamide (CNMa) is required for EAA hunger. Kim et al. investigated the mechanisms mediating the effects of CNMa and identified two complementary pathways mediating EAA preference (see the Perspective by Simpson and Raubenheimer). The first is a fast pathway triggered by neurons in the gut bearing a CNMa receptor, which in turn signals the brain to suppress the activity of sugar-sensing neurons. Second, a slower signal is induced by CNMa circulating through the hemolymph and ultimately reaching the brain. These results unveil feeding mechanisms essential for survival in Drosophila. —Mattia Maroso INTRODUCTION: Animals maintain nutrient homeostasis by adjusting feeding behavior according to internal nutritional needs. Protein intake is particularly critical because essential amino acids (EAAs) cannot be synthesized de novo and must be obtained from the diet. When dietary protein becomes limiting, animals develop a compensatory appetite that prioritizes protein-rich foods or EAA-containing foods. Although this adaptive behavior has been widely observed across species, the mechanisms by which animals respond to EAA deficiency and communicate this information to the brain remain poorly understood. RATIONALE: This study stemmed from our previous work demonstrating that CNMamide (CNMa), a peptide released from gut enterocytes, transmits the protein-hunger signal to the brain and mediates a selective appetite for EAAs. We focused on its receptor CNMaR, a G protein–coupled receptor that is expressed in enteric and brain neurons, among other cell types. We hypothesized that CNMaR+ neurons activated by CNMa during protein deprivation drive EAA-specific appetite. This hypothesis raises several important questions: (i) Are CNMaR+ neurons required for deprivation-induced EAA appetite, and if so, which CNMaR+ neuronal populations are involved? (ii) Through which route does CNMa convey the information from the gut to the brain? (iii) Is deprivation-induced EAA appetite conserved in mammals? Using genetic, physiological, and behavioral approaches in Drosophila and mice, we aimed to test this hypothesis and to address these key questions. RESULTS: Protein deprivation in Drosophila selectively increased preference for nutritive EAAs. An unbiased GAL4 screen and CaLexA (calcium-dependent nuclear import of LexA) labeling identified CNMaR+ ellipsoid body (EB) R3m neurons in the brain as key mediators of deprivation-induced EAA appetite. Silencing these neurons abolished EAA preference, whereas activating them was sufficient to induce EAA intake. These CNMaR+ neurons became more excitable during EAA deprivation and responded to CNMa through Gs-coupled CNMaR signaling. Likewise, CNMaR+ enteric neurons responded to CNMa and were both necessary and sufficient for the behavior. Notably, these enteric neurons transmit the protein-hunger signal directly to EB R3m neurons through a defined, cell type–specific gut-brain neuronal pathway. After this rapid gut-brain neuronal signaling, a slower hormonal pathway operates, in which circulating CNMa acts as a hormone stimulating CNMaR+ EB R3m neurons, thereby reinforcing and sustaining the gut-derived protein-hunger signal and EAA-specific appetite. Furthermore, CNMa signaling suppressed sugar intake by inhibiting diuretic hormone 44 (DH44)+ sugar-sensing neurons through Gi-coupled CNMaR signaling, thereby biasing feeding toward EAAs. Similar to these findings in flies, protein deprivation also induced a strong preference for EAAs in mice. Notably, this response persisted in the absence of fibroblast growth factor 21 (FGF21) signaling, which suggests that EAA-specific appetite is regulated independently of this established endocrine pathway. CONCLUSION: These findings identify gut-brain signaling systems that respond to protein deficiency and drive EAA-specific appetite. Gut-derived CNMa engages both neuronal and hormonal pathways to activate key neuronal populations that promote EAA intake while suppressing competing nutrients, such as carbohydrates. The observation that EAA-specific appetite is induced during protein deprivation independently of FGF21 in mice suggests the existence of previously unrecognized pathways regulating EAA-specific appetite, opening new directions for understanding the physiological mechanisms that maintain amino acid homeostasis. Protein deprivation triggers gut cells to release the peptide CNMa to activate CNMaR+ enteric neurons, initiating gut-brain communication in Drosophila.: CNMaR+ enteric neurons further enhance CNMa expression in the gut, thereby establishing a positive feedback loop that sustains EB R3 neuronal activity and promotes continued CNMa production. Gut-derived CNMa also directly activates EB R3 neurons while simultaneously suppressing DH44 neurons to inhibit carbohydrate intake. Ach, acetylcholine; ChAT, choline acetyltransferase. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | A deficit in dietary protein elicits a nutrient-specific appetite, yet the underlying mechanisms remain poorly understood. In this work, we identify coordinated neuronal and systemic mechanisms in Drosophila that drive an essential amino acid (EAA)–specific appetite. EAA deprivation increases neuropeptide CNMamide (CNMa) expression in gut enterocytes, activating enteric neurons and ellipsoid body neurons in the brain to promote EAA intake through two complementary pathways: a rapid neuronal gut-brain axis and a slower hormonal route. CNMa suppresses the activity of sugar-sensing diuretic hormone 44 (DH44) neurons, thereby reducing carbohydrate intake and biasing feeding toward EAAs. Similarly, protein deprivation in mice promotes an EAA-specific appetite independently of fibroblast growth factor 21 (FGF21). Together, these findings reveal multilayered gut-brain mechanisms that regulate nutrient-specific feeding and maintain EAA homeostasis across species. Editor's summary: A lack of sufficient dietary proteins leads to nutrient-specific appetite for essential amino acid (EAA)- or protein-rich food. In Drosophila, the peptide CNMamide (CNMa) is required for EAA hunger. Kim et al. investigated the mechanisms mediating the effects of CNMa and identified two complementary pathways mediating EAA preference (see the Perspective by Simpson and Raubenheimer). The first is a fast pathway triggered by neurons in the gut bearing a CNMa receptor, which in turn signals the brain to suppress the activity of sugar-sensing neurons. Second, a slower signal is induced by CNMa circulating through the hemolymph and ultimately reaching the brain. These results unveil feeding mechanisms essential for survival in Drosophila. —Mattia Maroso INTRODUCTION: Animals maintain nutrient homeostasis by adjusting feeding behavior according to internal nutritional needs. Protein intake is particularly critical because essential amino acids (EAAs) cannot be synthesized de novo and must be obtained from the diet. When dietary protein becomes limiting, animals develop a compensatory appetite that prioritizes protein-rich foods or EAA-containing foods. Although this adaptive behavior has been widely observed across species, the mechanisms by which animals respond to EAA deficiency and communicate this information to the brain remain poorly understood. RATIONALE: This study stemmed from our previous work demonstrating that CNMamide (CNMa), a peptide released from gut enterocytes, transmits the protein-hunger signal to the brain and mediates a selective appetite for EAAs. We focused on its receptor CNMaR, a G protein–coupled receptor that is expressed in enteric and brain neurons, among other cell types. We hypothesized that CNMaR+ neurons activated by CNMa during protein deprivation drive EAA-specific appetite. This hypothesis raises several important questions: (i) Are CNMaR+ neurons required for deprivation-induced EAA appetite, and if so, which CNMaR+ neuronal populations are involved? (ii) Through which route does CNMa convey the information from the gut to the brain? (iii) Is deprivation-induced EAA appetite conserved in mammals? Using genetic, physiological, and behavioral approaches in Drosophila and mice, we aimed to test this hypothesis and to address these key questions. RESULTS: Protein deprivation in Drosophila selectively increased preference for nutritive EAAs. An unbiased GAL4 screen and CaLexA (calcium-dependent nuclear import of LexA) labeling identified CNMaR+ ellipsoid body (EB) R3m neurons in the brain as key mediators of deprivation-induced EAA appetite. Silencing these neurons abolished EAA preference, whereas activating them was sufficient to induce EAA intake. These CNMaR+ neurons became more excitable during EAA deprivation and responded to CNMa through Gs-coupled CNMaR signaling. Likewise, CNMaR+ enteric neurons responded to CNMa and were both necessary and sufficient for the behavior. Notably, these enteric neurons transmit the protein-hunger signal directly to EB R3m neurons through a defined, cell type–specific gut-brain neuronal pathway. After this rapid gut-brain neuronal signaling, a slower hormonal pathway operates, in which circulating CNMa acts as a hormone stimulating CNMaR+ EB R3m neurons, thereby reinforcing and sustaining the gut-derived protein-hunger signal and EAA-specific appetite. Furthermore, CNMa signaling suppressed sugar intake by inhibiting diuretic hormone 44 (DH44)+ sugar-sensing neurons through Gi-coupled CNMaR signaling, thereby biasing feeding toward EAAs. Similar to these findings in flies, protein deprivation also induced a strong preference for EAAs in mice. Notably, this response persisted in the absence of fibroblast growth factor 21 (FGF21) signaling, which suggests that EAA-specific appetite is regulated independently of this established endocrine pathway. CONCLUSION: These findings identify gut-brain signaling systems that respond to protein deficiency and drive EAA-specific appetite. Gut-derived CNMa engages both neuronal and hormonal pathways to activate key neuronal populations that promote EAA intake while suppressing competing nutrients, such as carbohydrates. The observation that EAA-specific appetite is induced during protein deprivation independently of FGF21 in mice suggests the existence of previously unrecognized pathways regulating EAA-specific appetite, opening new directions for understanding the physiological mechanisms that maintain amino acid homeostasis. Protein deprivation triggers gut cells to release the peptide CNMa to activate CNMaR+ enteric neurons, initiating gut-brain communication in Drosophila.: CNMaR+ enteric neurons further enhance CNMa expression in the gut, thereby establishing a positive feedback loop that sustains EB R3 neuronal activity and promotes continued CNMa production. Gut-derived CNMa also directly activates EB R3 neurons while simultaneously suppressing DH44 neurons to inhibit carbohydrate intake. Ach, acetylcholine; ChAT, choline acetyltransferase. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adv3355 |
