Brain peptide ODN reduces hunger and boosts glucose regulation in rat study

University of Pennsylvania and Syracuse University scientists have discovered that a hindbrain-derived peptide, octadecaneuropeptide (ODN), can suppress appetite and improve glucose regulation without causing nausea or vomiting. Results suggest a glia-to-neuron signaling axis in the dorsal vagal complex that may be harnessed for treating obesity and type 2 diabetes.

Glial cells in the brainstem produce ODN, a signaling peptide whose physiological role in energy homeostasis has remained obscure. Researchers now find that directly activating this peptide system in the hindbrain induces weight loss, enhances glucose disposal, and lowers insulin resistance in obese animals.

Unlike existing therapies targeting GLP-1 receptors, ODN achieves these effects without triggering nausea-related behaviors or emesis in vomiting-competent models.

Obesity and type 2 diabetes are characterized by biological systems that maintain elevated fat mass and blood glucose as if they were normal. In obesity, weight loss can trigger counter-regulatory responses that increase hunger and reduce energy expenditure.

In type 2 diabetes, hepatic glucose output remains elevated even when blood glucose is already high. These maladaptive set points resist correction and complicate long-term treatment.

Central energy sensing is key to this rigidity. Brain regions such as the hypothalamus and the dorsal vagal complex (DVC) detect changes in circulating and gut-derived nutrient signals.

In healthy states, this system supports flexibility in energy intake and glucose disposal. In obesity and diabetes, this sensing is disrupted. As a result, the neural circuits that normally regulate homeostasis become biased toward maintaining excess.

Although much of the research has focused on neurons, glial cells, astrocytes and tanycytes have emerged as key players in nutrient sensing and energy balance.

Astrocytes respond to glucose deprivation and contribute to feeding suppression and glycemic regulation, particularly in the hindbrain. Tanycytes sense glucose, amino acids, and lipids, and mediate hormone access to the brain, including insulin and GLP-1 receptor agonists.

Both cell types produce the signaling peptide ODN, derived from diazepam binding inhibitor (DBI), in areas near the brain’s ventricles. Prior work has shown that ODN expression and release in the hypothalamus is stimulated by glucose and refeeding. Its function in the DVC has remained largely unexplored.

In the study, “Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis,” published in Science Translational Medicine, researchers designed a series of experiments to assess whether ODN signaling in the hindbrain regulates feeding, glycemia, and hormonal responses to glucose availability.

Experiments were conducted across rats, mice, and musk shrews using ODN and a modified analog, tridecaneuropeptide (TDN). Investigators further examined whether GLP-1 receptor agonists alter DBI expression and whether ODN signaling contributes to GLP-1–induced anorexia.

Researchers administered ODN or TDN via intracerebroventricular injection to the fourth or lateral ventricles to assess effects on food intake, glucose tolerance, insulin sensitivity, and hormone release.

Brain tissue was collected for immunofluorescence and in situ hybridization to quantify DBI expression in dorsal vagal complex subnuclei. Single-nucleus transcriptomic datasets were used to localize DBI transcripts across glial populations.

ODN suppressed food intake in rats maintained on chow or high-fat diets, with a more sustained anorectic effect and body weight reduction in diet-induced obese animals. Meal pattern analysis showed that ODN reduced meal size and duration in obese rats, while effects in lean rats were less pronounced.

ODN administration improved glucose tolerance and insulin sensitivity in lean and obese rats without increasing insulin secretion. Antagonism of the ODN receptor impaired glucose clearance and raised baseline glycemia.

In response to glucoprivation induced by 5-thio-D-glucose or insulin, ODN pretreatment reduced food intake, blunted hyperglycemia, and lowered circulating glucagon and free fatty acids without affecting corticosterone.

DBI mRNA expression in the dorsal vagal complex was upregulated by refeeding signals, including glucose and the GLP-1 receptor agonist exendin-4, with regional differences observed across subnuclei.

Blocking ODN signaling by antibody or receptor antagonist partially attenuated the anorectic effects of GLP-1 receptor agonists in chow and obese rats. These interventions did not alter GLP-1RA–induced kaolin intake or emesis, indicating that ODN contributes to appetite suppression but not malaise.

TDN improved glucose clearance and suppressed food intake when administered centrally. In obese mice, daily peripheral TDN injections induced sustained hypophagia and 4.7% body weight loss over nine days.

Hyperinsulinemic-euglycemic clamp studies confirmed increased glucose infusion rate and suppressed hepatic glucose production in TDN-treated mice.

Authors conclude that ODN produced in the dorsal vagal complex acts as a glial-derived signal of nutrient availability that regulates appetite, glucose disposal, and glucagon release.

Central ODN signaling suppressed food intake and improved glycemic control without triggering nausea or cardiovascular side effects. ODN expression increased in response to glucose and GLP-1 receptor agonists, and antagonizing its receptor impaired insulin sensitivity and blunted GLP-1RA–induced anorexia.

Systemic administration of a synthetic ODN derivative, TDN, mimicked these effects in obese rodents, reducing food intake and improving glucose metabolism. Importantly, neither central ODN nor TDN altered core body temperature, physical activity, or heart rate, underscoring their favorable safety profile.

Researchers propose that ODN’s receptor pathway may be targeted to achieve weight loss and metabolic improvements without the gastrointestinal intolerance often associated with current treatments for obesity and type 2 diabetes.

© 2025 Science X Network

University of Pennsylvania and Syracuse University scientists have discovered that a hindbrain-derived peptide, octadecaneuropeptide (ODN), can suppress appetite and improve glucose regulation without causing nausea or vomiting. Results suggest a glia-to-neuron signaling axis in the dorsal vagal complex that may be harnessed for treating obesity and type 2 diabetes.

Glial cells in the brainstem produce ODN, a signaling peptide whose physiological role in energy homeostasis has remained obscure. Researchers now find that directly activating this peptide system in the hindbrain induces weight loss, enhances glucose disposal, and lowers insulin resistance in obese animals.

Unlike existing therapies targeting GLP-1 receptors, ODN achieves these effects without triggering nausea-related behaviors or emesis in vomiting-competent models.

Obesity and type 2 diabetes are characterized by biological systems that maintain elevated fat mass and blood glucose as if they were normal. In obesity, weight loss can trigger counter-regulatory responses that increase hunger and reduce energy expenditure.

In type 2 diabetes, hepatic glucose output remains elevated even when blood glucose is already high. These maladaptive set points resist correction and complicate long-term treatment.

Central energy sensing is key to this rigidity. Brain regions such as the hypothalamus and the dorsal vagal complex (DVC) detect changes in circulating and gut-derived nutrient signals.

In healthy states, this system supports flexibility in energy intake and glucose disposal. In obesity and diabetes, this sensing is disrupted. As a result, the neural circuits that normally regulate homeostasis become biased toward maintaining excess.

Although much of the research has focused on neurons, glial cells, astrocytes and tanycytes have emerged as key players in nutrient sensing and energy balance.

Astrocytes respond to glucose deprivation and contribute to feeding suppression and glycemic regulation, particularly in the hindbrain. Tanycytes sense glucose, amino acids, and lipids, and mediate hormone access to the brain, including insulin and GLP-1 receptor agonists.

Both cell types produce the signaling peptide ODN, derived from diazepam binding inhibitor (DBI), in areas near the brain’s ventricles. Prior work has shown that ODN expression and release in the hypothalamus is stimulated by glucose and refeeding. Its function in the DVC has remained largely unexplored.

In the study, “Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis,” published in Science Translational Medicine, researchers designed a series of experiments to assess whether ODN signaling in the hindbrain regulates feeding, glycemia, and hormonal responses to glucose availability.

Experiments were conducted across rats, mice, and musk shrews using ODN and a modified analog, tridecaneuropeptide (TDN). Investigators further examined whether GLP-1 receptor agonists alter DBI expression and whether ODN signaling contributes to GLP-1–induced anorexia.

Researchers administered ODN or TDN via intracerebroventricular injection to the fourth or lateral ventricles to assess effects on food intake, glucose tolerance, insulin sensitivity, and hormone release.

Brain tissue was collected for immunofluorescence and in situ hybridization to quantify DBI expression in dorsal vagal complex subnuclei. Single-nucleus transcriptomic datasets were used to localize DBI transcripts across glial populations.

ODN suppressed food intake in rats maintained on chow or high-fat diets, with a more sustained anorectic effect and body weight reduction in diet-induced obese animals. Meal pattern analysis showed that ODN reduced meal size and duration in obese rats, while effects in lean rats were less pronounced.

ODN administration improved glucose tolerance and insulin sensitivity in lean and obese rats without increasing insulin secretion. Antagonism of the ODN receptor impaired glucose clearance and raised baseline glycemia.

In response to glucoprivation induced by 5-thio-D-glucose or insulin, ODN pretreatment reduced food intake, blunted hyperglycemia, and lowered circulating glucagon and free fatty acids without affecting corticosterone.

DBI mRNA expression in the dorsal vagal complex was upregulated by refeeding signals, including glucose and the GLP-1 receptor agonist exendin-4, with regional differences observed across subnuclei.

Blocking ODN signaling by antibody or receptor antagonist partially attenuated the anorectic effects of GLP-1 receptor agonists in chow and obese rats. These interventions did not alter GLP-1RA–induced kaolin intake or emesis, indicating that ODN contributes to appetite suppression but not malaise.

TDN improved glucose clearance and suppressed food intake when administered centrally. In obese mice, daily peripheral TDN injections induced sustained hypophagia and 4.7% body weight loss over nine days.

Hyperinsulinemic-euglycemic clamp studies confirmed increased glucose infusion rate and suppressed hepatic glucose production in TDN-treated mice.

Authors conclude that ODN produced in the dorsal vagal complex acts as a glial-derived signal of nutrient availability that regulates appetite, glucose disposal, and glucagon release.

Central ODN signaling suppressed food intake and improved glycemic control without triggering nausea or cardiovascular side effects. ODN expression increased in response to glucose and GLP-1 receptor agonists, and antagonizing its receptor impaired insulin sensitivity and blunted GLP-1RA–induced anorexia.

Systemic administration of a synthetic ODN derivative, TDN, mimicked these effects in obese rodents, reducing food intake and improving glucose metabolism. Importantly, neither central ODN nor TDN altered core body temperature, physical activity, or heart rate, underscoring their favorable safety profile.

Researchers propose that ODN’s receptor pathway may be targeted to achieve weight loss and metabolic improvements without the gastrointestinal intolerance often associated with current treatments for obesity and type 2 diabetes.

© 2025 Science X Network