The Metabolomic Effects of Tripeptide Gut Hormone Infusion Compared to Roux-en-Y Gastric Bypass and Caloric Restriction.

CONTEXT: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery. OBJECTIVE: To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). DESIGN AND SETTING: Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. PATIENTS AND INTERVENTIONS: Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. MAIN OUTCOME MEASURES: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention. RESULTS: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. CONCLUSIONS: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.

Combined GLP-1, Oxyntomodulin, and Peptide YY Improves Body Weight and Glycemia in Obesity and Prediabetes/Type 2 Diabetes: A Randomized, Single-Blinded, Placebo-Controlled Study.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity. RESEARCH DESIGN AND METHODS: In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also studied 21 patients who had undergone RYGB and 22 patients who followed a very low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and measures of glucose variability during continuous glucose monitoring. RESULTS: GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change -4.4 [95% CI -5.3, -3.5] kg) versus saline (-2.5 [-4.1, -0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (-44.1 [-62.7, -25.5] µmol/L) versus saline (-11.7 [-18.9, -4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD. CONCLUSIONS: GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes.

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of ß-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.

Antinociceptive profiles and mechanisms of centrally administered oxyntomodulin in various mouse pain models.

In the present study, the antinociceptive profiles of oxyntomodulin were examined in ICR mice. Oxyntomodulin administered intrathecally (i.t.) and intracerebroventricularly (i.c.v.) (from 1 to 5µg/5µl) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Moreover, cumulative response time of nociceptive behaviors induced by intraplantar formalin injection was reduced by i.t. or i.c.v. treatment with oxyntomodulin during the second, but not the first phase. In addition, the cumulative nociceptive response time after i.t. injection with substance P (0.7µg), glutamate (20µg), and pro-inflammatory cytokines such as TNF-α, IL-ß or IFN-γ (100pg/5µl) was diminished by spinally or supraspinally administered oxyntomodulin. However, i.t. and i.c.v. treatment with oxyntomodulin did not affect latencies of the tail-flick and hot-plate paw-licking responses. Furthermore, the i.t. pretreatment with yohimbine (adrenergic receptor antagonist), but not naloxone (an opioid receptor antagonist) or methysergide (a serotonergic receptor antagonist), attenuated antinociceptive effect induced by oxyntomodulin administered i.c.v. in the writhing test. The i.c.v. or i.t. pretreatment with oxyntomodulin attenuated formalin-induced increase of phosphorlated ERK (p-ERK) expression in the spinal cord. Our results suggest that centrally administered oxyntomodulin shows an antinociceptive property in various pain models except for thermal-induced nociception. Furthermore, supraspinally administered oxyntomodulin-induced antinociception may be mediated by spinal adrenergic receptors, but not serotonergic and opioidergic receptors. Furthermore, the antinociception induced by oxyntomodulin appears to be mediated by reduced formalin-induced p-ERK expression in the spinal cord.

Controlling the bioactivity of a peptide hormone in vivo by reversible self-assembly.

The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.

The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers.

Background: Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment of obesity, although limited by availability and operative risk. The gut hormones Glucagon-like peptide-1 (GLP-1), Peptide YY (PYY), and Oxyntomodulin (OXM) are elevated postprandially after RYGB, which has been postulated to contribute to its metabolic benefits. Objective: We hypothesized that infusion of the three gut hormones to achieve levels similar to those encountered postprandially in RYGB patients might be effective in suppressing appetite. The aim of this study was to investigate the effect of a continuous infusion of GLP-1, OXM, and PYY (GOP) on energy intake and expenditure in obese volunteers. Methods: Obese volunteers were randomized to receive an infusion of GOP or placebo in a single-blinded, randomized, placebo-controlled crossover study for 10.5 hours a day. This was delivered subcutaneously using a pump device, allowing volunteers to remain ambulatory. Ad libitum food intake studies were performed during the infusion, and energy expenditure was measured using a ventilated hood calorimeter. Results: Postprandial levels of GLP-1, OXM, and PYY seen post RYGB were successfully matched using 4 pmol/kg/min, 4 pmol/kg/min, and 0.4 pmol/kg/min, respectively. This dose led to a mean reduction of 32% in food intake. No significant effects on resting energy expenditure were observed. Conclusion: This is, to our knowledge, the first time that an acute continuous subcutaneous infusion of GOP, replicating the postprandial levels observed after RYGB, is shown to be safe and effective in reducing food intake. This data suggests that triple hormone therapy might be a useful tool against obesity.

Proglucagon-Derived Peptides Do Not Significantly Affect Acute Exocrine Pancreas in Rats.

OBJECTIVES: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. METHODS: Glucagon-like peptide 1, oxyntomodulin, glucagon, and exendin-4 were infused into anesthetized rats to measure plasma amylase concentration changes. In addition, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. RESULTS: Plasma amylase did not increase postpeptide infusion, compared with vehicle and cholecystokinin; however, oxyntomodulin inhibited plasma amylase when coadministered with cholecystokinin. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. CONCLUSIONS: The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin seems to be a potent inhibitor of amylase release, potentially making it a safer antiobesity agent regarding pancreatitis, compared with GLP-1 agonists.

Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease.

Oxyntomodulin is a hormone and a growth factor. It activates two receptors, the Glucagon-like peptide 1 (GLP-1) and the glucagon receptor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first positive results. D-Ser2-oxyntomodulin (Oxy) is a protease resistant oxyntomodulin analogue that has been developed to treat diabetes. Here we demonstrate for the first time that such analogues have neuroprotective effects. The drug showed protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected daily (20 mg/kg i.p.) for 7 days, and Oxy injected once-daily for 14 days i.p. Oxy treatment prevented or reversed the MPTP- induced motor impairment (Rotarod, spontaneous locomotion, swim activity, muscle strength test), the MPTP-induced reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, the reduction of the synaptic marker synapstophysin, the inactivation of the growth factor kinase Akt/PKB and of the anti-apoptotic signaling molecule Bcl-2, and the increase of levels of the pro-inflammatory cytokine TNF-α. The results demonstrate that oxyntomodulin analogues show promise as a novel treatment of PD.

Pulmonary delivery of anorectic oxyntomodulin in rats: food intake suppression, reduced body weight gain and pharmacokinetics.

BACKGROUND: Oxyntomodulin (OXM1-37) is an anorectic gut-secreting peptide with a promise to treat obesity, but its needle-free delivery has yet to be successful. RESULTS: Pulmonary delivery of OXM1-37, but not its C-terminal octapeptides, caused dose-related, transient 4-6 h food intake suppression in rats. At 0.5 mg/kg, its 30-38% food intake suppression led to 46% reduction in body weight gain by day 8. Its lung absorption was fast, elevating the systemic level rapidly, yet the bioavailability was low at 13%. In the brain, twofold neuronal c-fos activation was seen in the hypothalamus arcuate nucleus and brainstem area postrema. CONCLUSION: Pulmonary delivery is a promising needle-free systemic delivery option for OXM1-37 to treat obesity, as enabling effective lung absorption and brain interaction.

Intracerebroventricular administration of chicken oxyntomodulin suppresses food intake and increases plasma glucose and corticosterone concentrations in chicks.

Central administration of proglucagon-derived peptides, glucagon, glucagon-like peptide-1 (GLP-1), and oxyntomodulin (OXM), suppresses food intake in both mammals and birds. Recent findings suggest that GLP-1 receptor is involved in the anorexigenic action of OXM in both species. However, mammalian (bovine) OXM was used in chicken studies, even though the amino acid sequence and peptide length of chicken OXM differ from those of bovine OXM. In the present study, we examined the effect of chicken OXM on food intake and plasma components in chicks to investigate the mechanisms underlying the OXM effect. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken OXM significantly suppressed food intake in chicks. Plasma concentrations of glucose and corticosterone were significantly increased by chicken OXM. These phenomena were also observed after bovine OXM injection in chicks. In contrast, central administration of chicken GLP-1 significantly decreased plasma glucose concentration and did not affect plasma corticosterone concentration. We previously showed that central administration of chicken glucagon significantly increased plasma concentrations of glucose and corticosterone in chicks. All our findings suggest that the mechanism underlying the anorexigenic action of OXM is similar to that of glucagon in chicks.

Oxyntomodulin attenuates exendin-4-induced hypoglycemia in cattle.

Oxyntomodulin (OXM), glucagon, glucagon-like peptide-1 (GLP-1), and exendin-4 (Ex-4) are peptide hormones that regulate glucose homeostasis in monogastric and ruminant animals. Recently, we reported that the insulin-releasing effects of OXM and glucagon in cattle are mediated through both GLP-1 and glucagon receptors. The purpose of this study was to examine the mechanisms of the glucoregulatory actions induced by Ex-4, GLP-1, OXM, and glucagon and the interrelationships among these hormones in cattle. Two experiments were performed in Holstein cattle. In Experiment 1, we initially assessed the effects of intravenous (iv) bolus injection of 0, 0.25, 1, and 2 µg/kg body weight (BW) of Ex-4, GLP-1, and OXM on insulin and glucose concentrations in 3-mo-old intact male Holstein calves. In Experiment 2, we studied insulin and glucose responses to iv coinjection of 0.25 µg of Ex-4 or GLP-1/kg BW with 2 µg of OXM or glucagon/kg BW in 4-mo-old Holstein steers. Administration of peptides and blood sampling were done via a jugular catheter. Plasma was separated and the concentrations of peptides and glucose in plasma were analyzed using radioimmunoassay and enzymatic methods, respectively. Results showed that the potent glucoregulatory action of Ex-4 in 4-mo-old steers was delayed and attenuated when Ex-4 was coinjected with OXM. The decline in plasma glucose concentrations began at 5 min in the Ex-4-injected group (P < 0.05) vs 15 min in the Ex-4 + OXM-injected group (P < 0.05). Plasma concentrations of glucose at 30 min were reduced 26% from basal concentrations in the Ex-4-injected group and 13% in the Ex-4 + OXM-injected group (P < 0.001). Results also showed that the glucose concentrations initially increased in the Ex-4 + glucagon-treated group, but declined to a relatively hypoglycemic condition by 90 to 120 min. In contrast, the glucose concentrations at specific time points between the GLP-1 + OXM-injected group and the OXM-injected group did not differ. Similarly, the glucose concentrations in the GLP-1 + glucagon-injected group did not differ from those in the glucagon-injected group. Because OXM and glucagon mediate glucose concentrations via the glucagon receptor, it is suggested that the potent glucose-lowering action of Ex-4 might include the glucagon receptor antagonistic action of Ex-4.

PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.

OBJECTIVE: Peptide YY(3-36) (PYY(3-36)), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY(3-36) and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS: Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY(3-36) or oxyntomodulin or combined PYY(3-36)/oxyntomodulin. RESULTS: Energy intake during coadministration of PYY(3-36) and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS: The anorectic effects of PYY(3-36) and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Bifidobacterium as an oral delivery carrier of oxyntomodulin for obesity therapy: inhibitory effects on food intake and body weight in overweight mice.

INTRODUCTION: Oxyntomodulin (OXM) is a gut hormone released from intestinal L cell. Synthetic OXM and its analog reduce food intake and body weight in both rodents and human beings by being administered intravenously. However, people find intravenous administration difficult because of its side effects and inconvenience. The aim of this study is to develop a novel oral delivery system for OXM and its analog using genetically engineered Bifidobacterium as the carrier. METHODS: An OXM gene expression vector pBBADs-OXM for the Bifidobacterium genus was constructed. Human OXM sequence was fused with extracellular exo-xylanase (XynF) signal peptide (Xs) from Bifidobacterium longum under the control of the pBAD promoter. B. longum NCC2705 was transformed with the recombinant plasmid pBBADs-OXM by electroporation, and the transformed B. longum was selected using MRS plates containing 60 microg ml(-1) ampicillin. The OXM expression in vitro was identified by western blot and enzyme-linked immunosorbent assay (ELISA) assay after L-arabinose induction. Overweight BALB/c mice were treated with B. longum transformed with OXM after 0.2% L-arabinose induction every day for 4 weeks to investigate the effects of OXM-transformed B. longum on food intake and body weight by oral administration. The B. longum transformed with the green fluorescent protein (GFP) gene was used as negative control; orlistat, a gastrointestinal lipase inhibitor, was used as positive control; Normal saline (NS, 0.9% saline) was used as blank control. The food intakes of each group were measured every day, and body weights were measured once a week. Normal BALB/c (2 months old) mice were treated with OXM-transformed B. longum after induction by intragastric administration every day for 6 days to reveal the mechanism of transformed B. longum, with OXM exerting its biological function by oral administration. Plasma OXM, plasma ghrelin and the OXM of intestinal contents were detected by the ELISA method. Plasma glucose and triglyceride levels were analyzed using the Automatic Biochemistry Analyzer. RESULTS: Transformed B. longum with OXM was selected and identified without biological and morphological alteration. An approximately 4-5 kDa OXM peptide was detected in both the supernatant and the cell pellet of transformed B. longum after L-arabinose induction in vitro. The food intake, body weight and blood triglyceride level of overweight mice treated with OXM-transformed B. longum were all significantly reduced compared with that of the GFP negative control group and NS control group (P<0.01). Interestingly, the plasma triglyceride level of the GFP group was significantly decreased compared with that of the NS control group (P<0.01). The OXM level in the intestinal contents of the OXM group was significantly increased compared with that of the GFP negative control group and the NS group (P<0.05). The plasma ghrelin level of the OXM group was significantly decreased compared with that of the GFP and NS groups (P<0.01). Unexpectedly, the ghrelin level of the GFP group was significantly increased compared with that of the NS control group (P<0.01). CONCLUSION: A novel oral delivery system of Bifidobacterium for human OXM has been successfully established. The expression of recombinant OXM can be detected in the supernatant and cell pellet of transformed B. longum. OXM-transformed B. longum reduces food intake, body weight and plasma lipid level in overweight mice by oral administration.

[Expression of oxyntomodulin in bifidobacteria and effect of oxyntomodulin-transformed bifidobacteria on the body weight of obese mice].

OBJECTIVE: To observe the effect of pBBADs-OXM-transformed bifidobacteria on the body weight of obese mice. METHODS: B. longum was transformed with pBBADs-OXM by electroporation, and arabopyranose-induced oxyntomodulin expression by the bacterium was detected by ELISA. pBBADs-OXM-transformed bifidobacteria was administered orally obese mice on a daily basis with pBBADs-GFP-transformed bifidobacteria as the negative control, and the body weight changes of the mice were observed. RESULTS: OXM was detected by ELISA not only in the supernatant but also the precipitant of the transformed bacterial culture. The body weight of the obese mice fed with pBBADs-OXM-transformed bifidobacteria decreased significantly compared with that of the mice in the obese model group (P<0.05). CONCLUSION: Administration of pBBADs-OXM-transformed B.longum can reduce the body weight of obese mice.

Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice.

OBJECTIVE: Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist. RESEARCH DESIGN AND METHODS: We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r(-/-) and Gcgr(-/-) mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG. RESULTS: Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR. CONCLUSIONS: Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.

Hypothalamic injection of oxyntomodulin suppresses circulating ghrelin-like immunoreactivity.

Ghrelin is a gastric peptide that regulates appetite and GH secretion. Circulating ghrelin levels are elevated by fasting and suppressed postprandially. However, the mechanisms regulating circulating ghrelin levels are unclear. Oxyntomodulin is an anorexic peptide hormone released from L cells in the gut. We investigated the effects of intracerebroventricular (icv) administration of oxyntomodulin on circulating ghrelin levels. The icv administration of 1, 3, or 10 nmol oxyntomodulin reduced circulating acylated and total (acylated and des-acylated) ghrelin 60 min after icv injection. Administration of 1 nmol oxyntomodulin directly into the arcuate nucleus of the hypothalamus significantly reduced total and acylated ghrelin levels, and administration of 3 nmol oxyntomodulin into the lateral ventricle induced c-fos mRNA expression in arcuate nucleus neurons expressing the glucagon-like peptide-1 (GLP-1) receptor. In a final study, the reduction in total ghrelin observed after icv injection of 3 nmol oxyntomodulin was blocked by coadministration of the GLP-1 receptor antagonist exendin (9-39). These studies suggest oxyntomodulin reduces peripheral ghrelin levels via GLP-1 receptor-dependent hypothalamic pathways. Postprandial release of anorexic gut hormones may thus act centrally to contribute to the postprandial reduction in circulating ghrelin.

Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI).

We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.

Central oxyntomodulin causes anorexigenic effects associated with the hypothalamus and alimentary canal in chicks (Gallus gallus).

Several peptides that are derived from proglucagon including glucagon, glucagon-like peptide-1 (GLP-1), and oxyntomodulin (OXM) cause satiety in mammals. Glucagon and GLP-1 also cause satiety in the avian, but the effects of OXM on avian appetite-related processes are not reported. Thus, this study was conducted to elucidate whether OXM induces satiety in chicks and to determine its mechanism of induction. Intracerebroventricular (ICV) OXM, in a linear-dose dependent manner, potently decreased feed and water intake. However, we found that the effect on water intake was secondary to a reduction in feed intake. Chicks treated with ICV OXM had decreased c-Fos immunoreactivity in the regio lateralis hypothalami, but the nucleus infundibuli hypothalami (homologue to the mammalian arcuate nucleus) had increased c-Fos immunoreactivity. ICV OXM also caused total alimentary canal transit time to be decreased. We conclude that changes in the hypothalamus and gut may contribute to anorexigenic effects after ICV OXM in chicks. Through divergent evolution of birds and mammals, the central anorexigenic effects of OXM may have been conserved.

Co-administration of SR141716 with peptide YY3-36 or oxyntomodulin has additive effects on food intake in mice.

BACKGROUND: SR141716 has been shown to significantly inhibit food intake and reduce body weight by antagonizing CB(1) receptors. The gut hormones peptide YY(3-36) (PYY(3-36)) and oxyntomodulin (OXM) inhibit food intake through Y(2) and Glucagon-Like-Peptide (GLP)-1 receptors respectively. OBJECTIVE: To determine the effects of co-administration of SR141716 with either PYY(3-36) or OXM in mice on food intake. METHODS: Mice (n = 14 per group) were fasted for 16 h prior to study days and given two intraperitoneal injections: study 1, vehicle-saline, SR141716-saline, vehicle-PYY3-36 or SR141716-PYY3-36; study 2: vehicle-saline, SR141716-saline, vehicle-OXM or SR141716-OXM. Food was returned and measured following injections. RESULTS: Co-administration of SR141716-PYY(3-36) or SR141716-OXM showed greater inhibition in food intake when compared with administration of SR141716, PYY(3-36) or OXM alone. CONCLUSION: Our data show that SR141716 in combination with PYY(3-36) or OXM reduces food intake additively in mice.

Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging.

The anorexigenic gut hormones oxyntomodulin (OXM) and glucagon-like peptide-1 (GLP-1) are thought to physiologically regulate appetite and food intake. Using manganese-enhanced magnetic resonance imaging, we have shown distinct patterns of neuronal activation in the hypothalamus in response to intraperitoneal injections into fasted mice of 900 and 5400 nmol/kg OXM or 900 nmol/kg GLP-1. Administration of OXM at either dose resulted in a reduced rate of signal enhancement, reflecting a reduction in neuronal activity, in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus. Conversely, GLP-1 caused a reduction in signal enhancement in the paraventricular nucleus only and an increase in the ventromedial hypothalamic nucleus. Our data show that these two apparently similar peptides generate distinct patterns of activation within the hypothalamus, suggesting that GLP-1 and OXM may act via different hypothalamic pathways.