This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects' body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 ؎ 0.4 kg in the treatment group over the study period compared with 0.5 ؎ 0.5 kg in the control group (P ‫؍‬ 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 ؎ 37 kcal (25 ؎ 5%) at the initial study meal (P ‫؍‬ 0.0007) and by 250 ؎ 63 kcal (35 ؎ 9%) at the final study meal (P ‫؍‬ 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity. Diabetes 54: 2390 -2395, 2005 T he prevalence of obesity is rapidly increasing worldwide; currently Ͼ65% of adults in the U.S. are overweight (1). Although even a modest weight loss can improve the health of obese individuals, efforts to treat the obesity pandemic have been unsuccessful. Novel therapeutic targets are urgently required.Several gut hormones have been found to modulate appetite (2-4). Oxyntomodulin is a peptide product of the proglucagon gene released from the L-cells of the small intestine in response to food ingestion (5). Oxyntomodulin has been reported to reduce food intake by 19.3% during an intravenous infusion administered to normal-weight humans, an effect that continues for Ͼ12 h after infusion (6). Furthermore, in rodents, repeated intraperitoneal administration over 7 days has been associated with reduced white adipose tissue and a highly significant reduction in weight compared with controls (7). Thus, oxyntomodulin may offer a novel treatment for human obesity.We hypothesized that self-administered subcutaneous oxyntomodulin would induce weight loss, reduce appetite, and alter the levels of adipose hormones in overweight and obese volunteers investigated in a 4-week communitybased study. RESEARCH DESIGN AND METHODSHealthy male and female volunteers, ages 18 -55 years, with a stable BMI of 25-40 kg/m 2 were recruited by advertisement and followed between January and August 2004. All potential subjects were nonsmokers with normal physical examination, routine blood tests, and electrocardiograms. Subjects were screened using the standard Dutch Eating Behavior Questionnaire (8) and SCOFF Questionnaire (9) ...

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role. The aim of this review is to summarise the effects of different bariatric surgery procedures upon gastrointestinal and pancreatic peptides, including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic hormone (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin, insulin, glucagon and somatostatin.

. Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. Am J Physiol Endocrinol Metab 283: E1173-E1177, 2002. First published July 30, 2002 10.1152/ ajpendo.00233.2002 is a product of proglucagon processing in the intestine and the central nervous system. We reported that intracerebroventricular (ICV) and intranuclear administration of OXM caused an inhibition of food intake in rats (Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, and Bloom SR. Endocrinology 142: [4244][4245][4246][4247][4248][4249][4250] 2001). In this study, we investigated the effect of twice-daily ICV administration of OXM, 1 nmol, for 7 days. A pair-fed control was included. These animals were restricted to the food intake of the OXM group but injected twice daily with saline. OXM-treated animals gained significantly less weight than either control group (day 8: OXM, 12.2 Ϯ 1.9 g vs. pair fed, 21.0 Ϯ 2.1 g; P Ͻ 0.005). OXM treatment caused a reduction in epididymal white adipose tissue (OXM, 1.13 Ϯ 0.03 g vs. pair fed, 1.29 Ϯ 0.04 g; P Ͻ 0.05) and interscapular brown adipose tissue (OXM, 0.15 Ϯ 0.01 g vs. pair fed, 0.18 Ϯ 0.01 g; P Ͻ 0.05) and increased core temperature compared with saline control, suggestive of enhanced energy expenditure. The food restriction-induced suppression in plasma TSH, seen in the pair-fed group, was prevented by OXM, potentially via increased release of hypothalamic TRH. In summary, ICV OXM causes reduced body weight gain and body adiposity following chronic administration.glucagon-like peptide-1; energy expenditure; core temperature OXYNTOMODULIN (OXM) IS A PRODUCT of posttranslational processing of proglucagon in the intestine and central nervous system (CNS). Its amino acid sequence is highly conserved among species, which suggests an important physiological role. OXM is released from intestinal L cells in response to nutrient intake and is known to be a potent inhibitor of gastric acid secretion and gastric emptying in rodents and humans (7,22). OXM is also present in the hypothalamus, an area of the brain known to be involved in the regulation of appetite, body weight, and endocrine function. However, since its characterization and isolation in the early 1980s, little has been reported about the role of OXM within the CNS despite the apparent abundance of OXM peptide in the hypothalamus (3, 16).We have recently shown (6) that a single injection of OXM into the third cerebral ventricle (ICV) and into the hypothalamic paraventricular nucleus (PVN) causes a robust and sustained reduction of food intake in 24-h-fasted rats, associated with an increase in activity, indicating that the anorectic effect is not due to behavioral abnormalities.Glucagon-like peptide-1 (GLP-1) is another product of proglucagon processing in the intestine and the CNS and is a potential satiety factor (25, 26) and regulator of energy homeostasis (10,11,14). It has been hypothesized that OXM mediates its actions via the GLP-1 receptor (6,12,21). We have pr...