oxyntomodulin and Anorexia

Eating a meal is a mechanical process involving autonomous pathways that relay sensory and motor information between the whole length of the digestive tract and the central nervous system. This circuitry is able to initiate and terminate the meal, primarily by gut-brainstem-gut reflex arcs, and is independent of the caloric content of a meal. However, as part of our ability to regulate body weight over time, we must be able to modulate the amount of energy that we take in as food and the amount of energy that we expend. Thus, the gut-brainstem axis must be coupled to other systems that take account of factors such as food availability and preference, changing energy requirements and our social habits. Here, we review the importance of the brainstem nucleus of the tractus solitarius as a site of integration and the routes by which it connects the gut-brainstem axis with regulatory neuronal and endocrine networks that allow for strict body weight management.

Topics: Animals; Anorexia; Brain Stem; Eating; Glucagon-Like Peptides; Homeostasis; Hypothalamic Hormones; Neuropeptides; Peptides; Prolactin-Releasing Hormone; Solitary Nucleus

To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.. Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.. Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.. GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Topics: Agouti-Related Protein; Animals; Anorexia; Body Weight; Cholecystokinin; Eating; Glucagon-Like Peptides; Growth Differentiation Factor 15; Mice; Rats; Weight Loss

Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 microg of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 microg of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited.

Topics: Amygdala; Animals; Anorexia; Appetite Regulation; Behavior, Animal; Catheterization; Conditioning, Psychological; Dose-Response Relationship, Drug; Eating; Fourth Ventricle; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraperitoneal; Injections, Intraventricular; Lateral Ventricles; Lithium Chloride; Male; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Long-Evans; Receptors, Glucagon; Signal Transduction; Taste; Visceral Afferents

The present study examined possible interactions between central glucagon-like peptide-1 (GLP-1) and oxytocin (OT) neural systems by determining whether blockade of GLP-1 receptors attenuates OT-induced anorexia and vice versa. Male rats were acclimated to daily 4-h food access. In the first experiment, rats were infused centrally with GLP-1 receptor antagonist or vehicle, followed by an anorexigenic dose of synthetic OT. Access to food began 20 min later. Cumulative food intake was measured every 30 min for 4 h. In the second experiment, rats were infused with OT receptor blocker or vehicle, followed by synthetic GLP-1 [(7-36) amide]. Subsequent food intake was monitored as before. The anorexigenic effect of OT was eliminated in rats pretreated with the GLP-1 receptor antagonist. Conversely, GLP-1-induced anorexia was not affected by blockade of OT receptors. In a separate immunocytochemical study, OT-positive terminals were found closely apposed to GLP-1-positive perikarya, and central infusion of OT activated c-Fos expression in GLP-1 neurons. These findings implicate endogenous GLP-1 receptor signaling as an important downstream mediator of anorexia in rats after activation of central OT neural pathways.

Topics: Animals; Anorexia; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraventricular; Male; Neurons; Neurotransmitter Agents; Oxytocin; Peptide Fragments; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Receptors, Oxytocin; Signal Transduction

The present study sought to determine whether central glucagon-like peptide-1 (GLP-1)-receptor signalling contributes to the anorexigenic effects of systemically administered lithium chloride (LiCl). Male Sprague-Dawley rats with chronic intracerebroventricular (ICV) cannulas were acclimated to a feeding schedule that included daily 30-min access to palatable mash. In the first experiment, ICV infusion of a GLP-1-receptor antagonist [exendin-4-(3-39)] significantly attenuated (10 microgram dose) or completely blocked (20 microgram dose) the inhibition of food intake produced by subsequent ICV infusion of GLP-1-(7-36) amide (5 microgram). In the second experiment, rats were infused with 0, 10, or 20 microgram of the GLP-1-receptor antagonist ICV, followed by injection of 0.15 M LiCl (50 mg/kg ip) or the same volume of 0.15 M NaCl. The ability of LiCl treatment to suppress food intake was significantly attenuated in rats that were pretreated with the GLP-1-receptor antagonist. These results support the view that central mechanisms underlying LiCl-induced anorexia include a prominent role for endogenous GLP-1 neural pathways.

Topics: Animals; Anorexia; Brain; Dose-Response Relationship, Drug; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraventricular; Lithium Chloride; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Glucagon

Topics: Animals; Anorexia; Body Weight; Eating; Glucagon-Like Peptides; Leptin; Male; Melanocyte-Stimulating Hormones; Paraventricular Hypothalamic Nucleus; Peptides; Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptors, Corticotropin; Receptors, Melanocortin; Signal Transduction