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Stephen R Bloom - One of the best experts on this subject based on the ideXlab platform.
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Oxyntomodulin analogue increases energy expenditure via the glucagon receptor.
Peptides, 2018Co-Authors: Rebecca Scott, James Minnion, Tricia Tan, Stephen R BloomAbstract:The gut hormone Oxyntomodulin (OXM) causes weight loss by reducing appetite and increasing energy expenditure. Several analogues are being developed to treat obesity. Exactly how Oxyntomodulin works, however, remains controversial. OXM can activate both glucagon and GLP-1 receptors but no specific receptor has been identified. It is thought that the anorectic effect occurs predominantly through GLP-1 receptor activation but, to date, it has not been formally confirmed which receptor is responsible for the increased energy expenditure. We developed OX-SR, a sustained-release OXM analogue. It produces a significant and sustained increase in energy expenditure in rats as measured by indirect calorimetry. We now show that this increase in energy expenditure occurs via activation of the glucagon receptor. Blockade of the GLP-1 receptor with Exendin 9-39 does not block the increase in oxygen consumption caused by OX-SR. However, when activity at the glucagon receptor is lost, there is no increase in energy expenditure. Glucagon receptor activity therefore appears to be essential for OX-SR's effects on energy expenditure. The development of future 'dual agonist' analogues will require careful balancing of GLP-1 and glucagon receptor activities to obtain optimal effects.
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Increased food intake with Oxyntomodulin analogues
Peptides, 2015Co-Authors: Samantha L. Price, James Minnion, Stephen R BloomAbstract:Oxyntomodulin analogues offer a novel treatment for obesity. However during analogue screening in a rat model increased food intake was consistently observed. To further investigate this finding, a series of representative analogues (OXM14 and OXM15) and their Glu-3 equivalents (OXM14E3 and OXM15E3) were administered to rats for 7 days and food intake and bodyweight measurements taken. To investigate the role of glucagon receptor activation glutamate (Glu/E) was substituted at amino acid position 3. GLP-1 and glucagon receptor efficacy of the Oxyntomodulin analogues and their Glu-3 counterparts were measured at the rat receptors in vitro. Doses of 25 n mol/kg of OXM14 and OXM15 increased food intake by up to 20%. Bodyweight was not significantly increased. Food intake was not increased with the Glu-3 peptides, indicating that a glucagon receptor mechanism may be responsible for the increase in food intake.
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Hypothalamic Injection of Oxyntomodulin Suppresses Circulating Ghrelin-Like Immunoreactivity
Endocrinology, 2009Co-Authors: Michael Patterson, Kevin Murphy, Sejal R. Patel, N. A. Patel, Hannah C. Greenwood, Jenny H. Cooke, Daniel Campbell, Gavin A. Bewick, Mohammad A. Ghatei, Stephen R BloomAbstract: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.
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Gut Hormones as Potential New Targets for Appetite Regulation and the Treatment of Obesity
Drugs, 2008Co-Authors: Benjamin C. T. Field, Dunstan Cooke, Alison M Wren, Stephen R BloomAbstract:Food intake and bodyweight are tightly regulated by the brainstem, hypothalamus and reward circuits. These centres integrate diverse cognitive inputs with humoral and neuronal signals of nutritional status. Our knowledge of the role of gut hormones in this complex homeostatic system has expanded enormously in recent years. This review discusses both the role of gut hormones in appetite regulation, and the current state of development of gut hormone-based obesity therapies, with a particular focus on pancreatic polypeptide, peptide YY, amylin, glucagon-like peptide-1, Oxyntomodulin, cholecystokinin and ghrelin. Several gut hormone-based treatments for obesity are under investigation in phase II and III clinical trials, and many more are in the pipeline.
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Oxyntomodulin
Treatments in Endocrinology, 2006Co-Authors: Maralyn Druce, Stephen R BloomAbstract:The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on Oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context. Recent studies have shown that long-term peripheral administration of Oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, Oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity. The mechanism of action of Oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although Oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse. Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.
Andreea Soare - One of the best experts on this subject based on the ideXlab platform.
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The Mediterranean diet increases glucagon‐like peptide 1 and Oxyntomodulin compared with a vegetarian diet in patients with type 2 diabetes: A randomized controlled cross‐over trial
Diabetes Metabolism Research and Reviews, 2020Co-Authors: Antonio Di Mauro, Dario Tuccinardi, Mikiko Watanabe, Rossella Del Toro, Lavinia Monte, Riccardo Giorgino, Lorenzo Rampa, Giovanni Rossini, Shadi Kyanvash, Andreea SoareAbstract:AIM To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and Oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS GLP-1 and Oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and Oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and Oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.
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the mediterranean diet increases glucagon like peptide 1 and Oxyntomodulin compared with a vegetarian diet in patients with type 2 diabetes a randomized controlled cross over trial
Diabetes-metabolism Research and Reviews, 2020Co-Authors: Antonio Di Mauro, Dario Tuccinardi, Mikiko Watanabe, Rossella Del Toro, Lavinia Monte, Riccardo Giorgino, Lorenzo Rampa, Giovanni Rossini, Shadi Kyanvash, Andreea SoareAbstract:AIM To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and Oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS GLP-1 and Oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and Oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and Oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.
Anders Sjödin - One of the best experts on this subject based on the ideXlab platform.
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Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Mette S. Nielsen, Jens J. Holst, Christian Ritz, Nicolai Wewer J Albrechtsen, Carel Le W Roux, Anders SjödinAbstract:BACKGROUND Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences. METHODS Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, Oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery. RESULTS Postprandial concentrations of glicentin, Oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and Oxyntomodulin predicted a greater weight loss (both P < .01) and were associated with a larger decrease in energy density (P ≤ .04). No associations were found for GLP-1, PYY, and ghrelin, and changes were not associated with changes in energy intake. When combing all hormones, 60%, 19%, and 33% of the variations in weight loss, energy intake, and energy density, respectively, could be explained. CONCLUSION Postprandial responses of gastrointestinal hormones differed between RYGB and SG. Enhanced responses of glicentin and Oxyntomodulin predicted a better weight loss and were associated with a decreased preference for energy-dense foods. Replication of these results could imply an opportunity to identify patients in need of additional support after surgical treatments of obesity.
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Oxyntomodulin and Glicentin May Predict the Effect of Bariatric Surgery on Food Preferences and Weight Loss.
The Journal of Clinical Endocrinology & Metabolism, 2020Co-Authors: Mette S. Nielsen, Jens J. Holst, Nicolai J. Wewer Albrechtsen, Christian Ritz, Carel W. Le Roux, Anders SjödinAbstract:BACKGROUND Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences. METHODS Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, Oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery. RESULTS Postprandial concentrations of glicentin, Oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and Oxyntomodulin predicted a greater weight loss (both P
Jens J. Holst - One of the best experts on this subject based on the ideXlab platform.
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Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Mette S. Nielsen, Jens J. Holst, Christian Ritz, Nicolai Wewer J Albrechtsen, Carel Le W Roux, Anders SjödinAbstract:BACKGROUND Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences. METHODS Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, Oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery. RESULTS Postprandial concentrations of glicentin, Oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and Oxyntomodulin predicted a greater weight loss (both P < .01) and were associated with a larger decrease in energy density (P ≤ .04). No associations were found for GLP-1, PYY, and ghrelin, and changes were not associated with changes in energy intake. When combing all hormones, 60%, 19%, and 33% of the variations in weight loss, energy intake, and energy density, respectively, could be explained. CONCLUSION Postprandial responses of gastrointestinal hormones differed between RYGB and SG. Enhanced responses of glicentin and Oxyntomodulin predicted a better weight loss and were associated with a decreased preference for energy-dense foods. Replication of these results could imply an opportunity to identify patients in need of additional support after surgical treatments of obesity.
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Oxyntomodulin and Glicentin May Predict the Effect of Bariatric Surgery on Food Preferences and Weight Loss.
The Journal of Clinical Endocrinology & Metabolism, 2020Co-Authors: Mette S. Nielsen, Jens J. Holst, Nicolai J. Wewer Albrechtsen, Christian Ritz, Carel W. Le Roux, Anders SjödinAbstract:BACKGROUND Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences. METHODS Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, Oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery. RESULTS Postprandial concentrations of glicentin, Oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and Oxyntomodulin predicted a greater weight loss (both P
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Oxyntomodulin: Actions and role in diabetes.
Peptides, 2018Co-Authors: Jens J. Holst, Nicolai J. Wewer Albrechtsen, Maria Buur Nordskov Gabe, Mette M. RosenkildeAbstract:Abstract Oxyntomodulin is a product of the glucagon precursor, proglucagon, produced and released from the endocrine L-cells of the gut after enzymatic processing by the precursor prohormone convertase 1/3. It corresponds to the proglucagon sequence 33–69 and thus contains the entire glucagon sequence plus a C-terminal octapeptide, comprising in total 37 amino acids. As might have been expected, it has glucagon-like bioactivity, but also and more surprisingly also activates the receptor for GLP-1. This has given the molecule an interesting status as a glucagon-GLP-1 co-agonist, which is currently attracting considerable interest for its potential in the treatment of diabetes and obesity. Here, we provide an update on Oxyntomodulin with a focus on its potential role in metabolic diseases.
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Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure
The Journal of Clinical Endocrinology & Metabolism, 2015Co-Authors: Jonatan I. Bagger, Jens J. Holst, Bolette Hartmann, Filip K. Knop, Birgitte Andersen, Tina VilsbøllAbstract:Context: The gut hormone, Oxyntomodulin, is a proglucagon product with body weight-lowering potential. It binds to both the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor; however, the mechanism behind the body weight-lowering effect remains elusive. Objective: We wanted to delineate the contributions of separate and combined GLP-1 receptor and glucagon receptor activation to the body weight-reducing mechanisms of Oxyntomodulin. Design: This was a double-blinded, randomized, crossover study. Setting: The study was conducted at a specialized research unit. Participants: Fifteen young healthy male volunteers (aged 22 [range 18–32] y; body mass index 23 [21–26] kg/m2; fasting plasma glucose 5.1 [4.4–5.4] mmol/L; and glycated hemoglobin A1c 40 (37–42) mmol/mol). Interventions: Five 4-hour liquid meal tests during the infusion of saline, GLP-1 (1 pmol × kg−1 × min−1), glucagon (0.86 pmol × kg−1 × min−1), Oxyntomodulin (3 pmol × kg−1 × min−1), or glucagon+GLP-1 (same doses). Main Outcome Mea...
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Specificity and sensitivity of commercially available assays for glucagon and Oxyntomodulin measurement in humans
European Journal of Endocrinology, 2014Co-Authors: Monika Judyta Bak, Nicolai J. Wewer Albrechtsen, Jens Pedersen, Bolette Hartmann, Mikkel B. Christensen, Tina Vilsbøll, Filip K. Knop, Carolyn F. Deacon, Lars O. Dragsted, Jens J. HolstAbstract:AIM To determine the specificity and sensitivity of assays carried out using commercially available kits for glucagon and/or Oxyntomodulin measurements. METHODS Ten different assay kits used for the measurement of either glucagon or Oxyntomodulin concentrations were obtained. Solutions of synthetic glucagon (proglucagon (PG) residues 3361), Oxyntomodulin (PG residues 3369) and glicentin (PG residues 169) were prepared and peptide concentrations were verified by quantitative amino acid analysis and a processing-independent in-house RIA. Peptides were added to the matrix (assay buffer) supplied with the kits (concentration range: 1.25-300 pmol/l) and to human plasma and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations. RESULTS AND CONCLUSION Three assays were specific for glucagon (carried out using the Millipore (Billerica, MA, USA), Bio-Rad (Sundbyberg, Sweden), and ALPCO (Salem, NH, USA) and Yanaihara Institute (Shizuoka, Japan) kits), but none was specific for Oxyntomodulin. The assay carried out using the Phoenix (Burlingame, CA, USA) glucagon kit measured the concentrations of all three peptides (total glucagon) equally. Sensitivity and precision were generally poor; the assay carried out using the Millipore RIA kit performed best with a sensitivity around 10 pmol/l. Assays carried out using the BlueGene (Shanghai, China), USCN LIFE (Wuhan, China) (Oxyntomodulin and glucagon), MyBioSource (San Diego, CA, USA) and Phoenix Oxyntomodulin kits yielded inconsistent results.
Carel Le W Roux - One of the best experts on this subject based on the ideXlab platform.
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Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Mette S. Nielsen, Jens J. Holst, Christian Ritz, Nicolai Wewer J Albrechtsen, Carel Le W Roux, Anders SjödinAbstract:BACKGROUND Alterations in several gastrointestinal hormones are implicated in the postoperative suppression of food intake leading to weight loss after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The aim was to evaluate changes in responses of gastrointestinal hormones after RYGB and SG and the associations of these changes with weight loss, energy intake, and food preferences. METHODS Forty-two subjects with severe obesity were included (32 RYGB; 10 SG). Postprandial responses of glicentin, Oxyntomodulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin were measured before and 6 months after surgery. Energy intake and energy density were assessed before and 6 months after surgery using a buffet meal test and weight loss was assessed 18 months after surgery. RESULTS Postprandial concentrations of glicentin, Oxyntomodulin, GLP-1, and ghrelin differed between RYGB and SG (all P ≤ .02). Enhanced responses of glicentin and Oxyntomodulin predicted a greater weight loss (both P < .01) and were associated with a larger decrease in energy density (P ≤ .04). No associations were found for GLP-1, PYY, and ghrelin, and changes were not associated with changes in energy intake. When combing all hormones, 60%, 19%, and 33% of the variations in weight loss, energy intake, and energy density, respectively, could be explained. CONCLUSION Postprandial responses of gastrointestinal hormones differed between RYGB and SG. Enhanced responses of glicentin and Oxyntomodulin predicted a better weight loss and were associated with a decreased preference for energy-dense foods. Replication of these results could imply an opportunity to identify patients in need of additional support after surgical treatments of obesity.
