College of Pennsylvania and Syracuse College scientists have found {that a} hindbrain-derived peptide, octadecaneuropeptide (ODN), can suppress urge for food and enhance glucose regulation with out inflicting nausea or vomiting. Outcomes recommend a glia-to-neuron signaling axis within the dorsal vagal complicated that could be harnessed for treating weight problems and kind 2 diabetes.
Glial cells within the brainstem produce ODN, a signaling peptide whose physiological function in power homeostasis has remained obscure. Researchers now discover that immediately activating this peptide system within the hindbrain induces weight reduction, enhances glucose disposal, and lowers insulin resistance in overweight animals.
In contrast to present therapies focusing on GLP-1 receptors, ODN achieves these results with out triggering nausea-related behaviors or emesis in vomiting-competent fashions.
Weight problems and kind 2 diabetes are characterised by organic programs that preserve elevated fats mass and blood glucose as in the event that they have been regular. In weight problems, weight reduction can set off counter-regulatory responses that enhance starvation and cut back power expenditure.
In sort 2 diabetes, hepatic glucose output stays elevated even when blood glucose is already excessive. These maladaptive set factors resist correction and complicate long-term remedy.
Central power sensing is essential to this rigidity. Mind areas such because the hypothalamus and the dorsal vagal complicated (DVC) detect adjustments in circulating and gut-derived nutrient indicators.
In wholesome states, this technique helps flexibility in power consumption and glucose disposal. In weight problems and diabetes, this sensing is disrupted. Consequently, the neural circuits that usually regulate homeostasis change into biased towards sustaining extra.
Though a lot of the analysis has targeted on neurons, glial cells, astrocytes and tanycytes have emerged as key gamers in nutrient sensing and power stability.
Astrocytes reply to glucose deprivation and contribute to feeding suppression and glycemic regulation, significantly within the hindbrain. Tanycytes sense glucose, amino acids, and lipids, and mediate hormone entry to the mind, together with insulin and GLP-1 receptor agonists.
Each cell varieties produce the signaling peptide ODN, derived from diazepam binding inhibitor (DBI), in areas close to the mind’s ventricles. Prior work has proven that ODN expression and launch within the hypothalamus is stimulated by glucose and refeeding. Its perform within the DVC has remained largely unexplored.
Within the examine, “Hindbrain octadecaneuropeptide gliotransmission as a therapeutic goal for power stability management with out nausea or emesis,” revealed in Science Translational Medication, researchers designed a sequence of experiments to evaluate whether or not ODN signaling within the hindbrain regulates feeding, glycemia, and hormonal responses to glucose availability.
Experiments have been performed throughout rats, mice, and musk shrews utilizing ODN and a modified analog, tridecaneuropeptide (TDN). Investigators additional examined whether or not GLP-1 receptor agonists alter DBI expression and whether or not ODN signaling contributes to GLP-1–induced anorexia.
Researchers administered ODN or TDN by way of intracerebroventricular injection to the fourth or lateral ventricles to evaluate results on meals consumption, glucose tolerance, insulin sensitivity, and hormone launch.
Mind tissue was collected for immunofluorescence and in situ hybridization to quantify DBI expression in dorsal vagal complicated subnuclei. Single-nucleus transcriptomic datasets have been used to localize DBI transcripts throughout glial populations.
ODN suppressed meals consumption in rats maintained on chow or high-fat diets, with a extra sustained anorectic impact and physique weight discount in diet-induced overweight animals. Meal sample evaluation confirmed that ODN decreased meal measurement and length in overweight rats, whereas results in lean rats have been much less pronounced.
ODN administration improved glucose tolerance and insulin sensitivity in lean and overweight rats with out rising 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 decreased meals consumption, blunted hyperglycemia, and lowered circulating glucagon and free fatty acids with out affecting corticosterone.
DBI mRNA expression within the dorsal vagal complicated was upregulated by refeeding indicators, together with glucose and the GLP-1 receptor agonist exendin-4, with regional variations noticed throughout subnuclei.
Blocking ODN signaling by antibody or receptor antagonist partially attenuated the anorectic results of GLP-1 receptor agonists in chow and overweight rats. These interventions didn’t alter GLP-1RA–induced kaolin consumption or emesis, indicating that ODN contributes to urge for food suppression however not malaise.
TDN improved glucose clearance and suppressed meals consumption when administered centrally. In overweight mice, each day peripheral TDN injections induced sustained hypophagia and 4.7% physique weight reduction over 9 days.
Hyperinsulinemic-euglycemic clamp research confirmed elevated glucose infusion fee and suppressed hepatic glucose manufacturing in TDN-treated mice.
Authors conclude that ODN produced within the dorsal vagal complicated acts as a glial-derived sign of nutrient availability that regulates urge for food, glucose disposal, and glucagon launch.
Central ODN signaling suppressed meals consumption and improved glycemic management with out triggering nausea or cardiovascular unintended effects. ODN expression elevated 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 an artificial ODN by-product, TDN, mimicked these results in overweight rodents, decreasing meals consumption and enhancing glucose metabolism. Importantly, neither central ODN nor TDN altered core physique temperature, bodily exercise, or coronary heart fee, underscoring their favorable security profile.
Researchers suggest that ODN’s receptor pathway could also be focused to realize weight reduction and metabolic enhancements with out the gastrointestinal intolerance usually related to present remedies for weight problems and kind 2 diabetes.
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Extra data:
Caroline E. Geisler et al, Hindbrain octadecaneuropeptide gliotransmission as a therapeutic goal for power stability management with out nausea or emesis, Science Translational Medication (2025). DOI: 10.1126/scitranslmed.adu6764
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Mind peptide ODN reduces starvation and boosts glucose regulation in rat examine (2025, July 26)
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