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Obesity
Published in Geoffrey P. Webb, Nutrition, 2019
In the last chapter, several gut hormones were noted as having appetite suppressing effects and so drugs that mimic the actions of these hormones might have potential as anti-obesity agents. Cholecystokinin (CCK) is a gut hormone released during feeding that causes satiety and it is also a transmitter in the brain where it also seems to depress feeding. Despite early promise, CCK has limited potential as an obesity agent because animals rapidly adapt to excess CCK and become tolerant to it and even when animals are born lacking CCK receptors they are still able to regulate their body weight normally. Oxyntomodulin may have potential as an anti-obesity agent and in experimental studies it decreases body weight by both reducing energy intake and increasing expenditure. Suzuki et al. (2011) reviewed the role of gut hormones in appetite regulation. They suggested that changes in gut hormone levels may contribute to the long-term successes of some surgical treatments for obesity. Following gastric banding, there is a decrease in the level of the appetite-stimulating hormone ghrelin and increases in some gut hormones that have anorectic effects. They suggest that mimicking the changes in gut hormone levels produced by obesity surgery could also produce weight reduction. None of this research has yet produced a marketable obesity treatment.
Central and Peripheral Modulators of Appetite and Satiety
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Gabrielle Page-Wilson, Sam Dagogo-Jack
Oxyntomodulin (OXM) is produced from prepro-glucagon, mainly in the endocrine L-cells of the gut, and is secreted with GLP-1 following nutrient ingestion (Drucker 2005). This peptide hormone is composed of 37 amino acids, with sequence homology to GLP-1 and glucagon (Holst 1983). OXM has an affinity for GLP-1 and the glucagon receptor (Gros et al. 1993, Holst 1997) and, in addition to acutely inhibiting gastric emptying and gastric and pancreatic exocrine secretion, OXM has been shown to inhibit food intake and increase energy expenditure in both rodents and humans (Schjoldager et al. 1988, Dakin et al. 2001, Wynne et al. 2005, 2006, Bagger et al. 2015). In a randomized, controlled trial, an average weight loss of 2.3 kg was observed in overweight and obese subjects treated with subcutaneous OXM for 4 weeks, as compared to a 0.5-kg weight loss with placebo. Additionally, OXM infusions have been shown to improve glucose metabolism in type 2 diabetes (Shankar 2013). Given the therapeutic potential for native OXM to promote weight loss and glucose control, the therapeutic possibilities of stimulating endogenous OXM secretion, or synthesizing analogues, are currently receiving attention (Pocai 2014).
Approach to the Overweight and Obese Patient
Published in David Heber, Zhaoping Li, Primary Care Nutrition, 2017
The ileal brake is a feedback phenomenon whereby ingested food activates distal-intestinal signals that inhibit proximal GI motility and gastric emptying (Pironi et al. 1993). It is mediated by neural mechanisms and several peptides that are also implicated in satiation. These signals act to put a behavior brake on eating to supplement the ileal brake’s actions and reduce the rate of nutrient entry into the bloodstream (Strader and Woods 2005). Glucagon-like peptide 1 (GLP-1) is cleaved from proglucagon, expressed in the gut, pancreas, and brain (Drucker 2006). Other proglucagon products include glucagon (a counterregulatory hormone), GLP-2 (an intestinal growth factor), glicentin (a gastric acid inhibitor), and oxyntomodulin. The strongest evidence for satiety effects have been found for GLP-1 and oxyntomodulin. Like GLP-1, oxyntomodulin is a proglucagon-derived peptide secreted from distal-intestinal L-cells in proportion to ingested calories. PYY is produced mainly by distal-intestinal L-cells, most of which coexpress GLP-1. It is secreted after meals in proportion to caloric load, with a macronutrient potency of lipids being greater than that of carbohydrates, which is greater than that of proteins (Degen et al. 2005).
Pharmacological profile of once-weekly injectable semaglutide for chronic weight management
Published in Expert Review of Clinical Pharmacology, 2022
David C. W. Lau, Rachel L Batterham, Carel W. le Roux
Another class of co-agonists, the dual GLP-1 and glucagon receptor co-agonist, is currently in phase 1 and 2 clinical trials [65,66]. The rationale for pursuing the development of a dual GLP-1 and glucagon receptor co-agonist is to exploit the stimulatory effect of glucagon on energy expenditure, which might lead to greater weight loss than can be achieved through central appetite suppression with a GLP-1 RA alone. Oxyntomodulin is a naturally occurring gut hormone that activates both GLP-1 and glucagon receptors and has a potent effect on energy balance and body weight regulation. Oxyntomodulin analogs are unimolecular dual co-agonists that promote weight loss through distinct mechanisms of action [66]. Unimolecular triple incretins, combining GLP-1, GIP, and glucagon receptor tri-agonist, are also under active investigation for obesity and diabetes treatment [67].
Novel approaches to anti-obesity drug discovery with gut hormones over the past 10 years
Published in Expert Opinion on Drug Discovery, 2019
Frances Rose, Stephen Bloom, Tricia Tan
Oxyntomodulin (OXM) is a peptide hormone also produced by the post-translational processing of proglucagon in the gut. It differs in structure from glucagon by the inclusion of a C-terminal octapeptide [65]. OXM is co-secreted with GLP-1 from neuroendocrine L-cells in the intestine, and is a unimolecular agonist for both the GLP1R and the GCGR [66]. The dual agonism of OXM produces superior reduction in food intake, as well as a significantly higher reduction in body weight and fat mass than a pure GLP1R agonist [66]. A double blind, placebo controlled parallel group study showed a reduction in body weight of 2.4% in overweight and obese volunteers when given a pre-prandial subcutaneous injection of OXM for 4 weeks [67]. Due to the intrinsic dual receptor activity of OXM, structural modifications to improve the half life and increase the potency have been explored. A PEGylated long-acting GLP1R/GCGR co-agonist has been shown to improve glycaemic control, reduce food intake and induce substantial weight loss in mice with diet-induced obesity when given once a week [68].
Emerging PEGylated non-biologic drugs
Published in Expert Opinion on Emerging Drugs, 2019
Eun Ji Park, Jiyoung Choi, Kang Choon Lee, Dong Hee Na
TT401 (LY2944876) is a once-weekly oxyntomodulin analog with dual glucagon-like peptide-1 (GLP-1) and glucagon receptors agonist activity, which is under development by Transition Therapeutics Inc. for the treatment of type 2 diabetes and accompanying obesity [79]. Oxyntomodulin is a naturally occurring 37-amino acid peptide hormone released from the gut with GLP-1 in the post-prandial state, which is a dual agonist that activates both GLP-1 and glucagon receptors, resulting in the reduction of body weight through increased energy expenditure and reduced food intake [80]. In phase 2 clinical study, TT401 showed dose-dependent body weight loss after 12 and 24 weeks of treatment and provided HbA1c reduction of up to −1.43%, similar to that of exenatide (ClinicalTrials.gov identifier: NCT02119819). This clinical study also demonstrated that TT401 had an acceptable safety and tolerability profile, consistent with GLP-1 single agonists.