Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in ß-arrestin 1/2 signaling.

Glucagon-like peptide-1 receptor (GLP-1R) is a prime drug target for type 2 diabetes and obesity. The ligand initiated GLP-1R interaction with G protein has been well studied, but not with ß-arrestin 1/2. Therefore, bioluminescence resonance energy transfer (BRET), mutagenesis and an operational model were used to evaluate the roles of 85 extracellular surface residues on GLP-1R in ß-arrestin 1/2 recruitment triggered by three representative GLP-1R agonists (GLP-1, exendin-4 and oxyntomodulin). Residues selectively regulated ß-arrestin 1/2 recruitment for diverse ligands, and ß-arrestin isoforms were identified. Mutation of residues K130-S136, L142 and Y145 on the transmembrane helix 1 (TM1)-extracellular domain (ECD) linker decreased ß-arrestin 1 recruitment but increased ß-arrestin 2 recruitment. Other extracellular loop (ECL) mutations, including P137A, Q211A, D222A and M303A selectively affected ß-arrestin 1 recruitment while D215A, L217A, Q221A, S223A, Y289A, S301A, F381A and I382A involved more in ß-arrestin 2 recruitment for the ligands. Oxyntomodulin engaged more broadly with GLP-1R extracellular surface to drive ß-arrestin 1/2 recruitment than GLP-1 and exendin-4; I147, W214 and L218 involved in ß-arrestin 1 recruitment, while L141, D215, L218, D293 and F381 in ß-arrestin 2 recruitment for oxyntomodulin particularly. Additionally, the non-conserved residues on ß-arrestin 1/2 C-domains contributed to interaction with GLP-1R. Further proteomic profiling of GLP-1R stably expressed cell line upon ligand stimulation with or without ß-arrestin 1/2 overexpression demonstrated both commonly and biasedly regulated proteins and pathways associated with cognate ligands and ß-arrestins. Our study offers valuable information about ligand induced ß-arrestin recruitment mediated by GLP-1R and consequent intracellular signaling events.

Perspectives in weight control in diabetes - Survodutide.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved treatments for Type 2 diabetes mellitus, with liraglutide and semaglutide also approved for the treatment of obesity. The natural gut hormone oxyntomodulin is a weak dual agonist of the glucagon receptor (GCGR) and GLP-1R. Development of poly-agonists mimicking oxyntomodulin, such as the novel dual GCGR/GLP-1R agonist survodutide, represents an important step towards a more effective treatment for people with Type 2 diabetes mellitus and obesity. Survodutide is a 29-amino acid peptide derived from glucagon, with the incorporation of potent GLP-1 activities. It contains a C18 diacid which mediates binding to albumin, thereby prolonging the half-life to enable once-weekly subcutaneous dosing. The utilisation of GCGR agonism aims to enhance body weight-lowering effects by increasing energy expenditure in addition to the anorectic action of GLP-1R agonists. Glucose-lowering efficacy of survodutide has been demonstrated in a Phase II trial in patients with Type 2 diabetes mellitus and obesity and was associated with clinically meaningful body weight loss. These data highlight the potential of dual GCGR/GLP-1R agonism for reducing glycated haemoglobin and body weight in patients with Type 2 diabetes mellitus, and for greater therapeutic efficacy compared with GLP-1R agonism alone.

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes.

OBJECTIVE: Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS: The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS: OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION: These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.

Self-assembled GLP-1/glucagon peptide nanofibrils prolong inhibition of food intake.

Introduction: Oxyntomodulin (Oxm) hormone peptide has a number of beneficial effects on nutrition and metabolism including increased energy expenditure and reduced body weight gain. Despite its many advantages as a potential therapeutic agent, Oxm is subjected to rapid renal clearance and protease degradation limiting its clinical application. Previously, we have shown that subcutaneous administration of a fibrillar Oxm formulation can significantly prolong its bioactivity in vivo from a few hours to a few days. Methods: We used a protease resistant analogue of Oxm, Aib2-Oxm, to form nanfibrils depot and improve serum stability of released peptide. The nanofibrils and monomeric peptide in solution were characterized by spectroscopic, microscopic techniques, potency assay, QCM-D and in vivo studies. Results: We show that in comparison to Oxm, Aib2-Oxm fibrils display a slower elongation rate requiring higher ionic strength solutions, and a higher propensity to dissociate. Upon subcutaneous administration of fibrillar Aib2-Oxm in rodents, a 5-fold increase in bioactivity relative to fibrillar Oxm and a significantly longer bioactivity than free Aib2-Oxm were characterized. Importantly, a decrease in food intake was observed up to 72-hour post-administration, which was not seen for free Aib2-Oxm. Conclusion: Our findings provides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced in vivo pharmacological response.

Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity.

Oxyntomodulin (OXM) is an endogenous peptide hormone secreted from the intestines following nutrient ingestion that activates both glucagon-like peptide-1 (GLP-1) and glucagon receptors. OXM is known to exert various effects, including improvement in glucose tolerance, promotion of energy expenditure, acceleration of liver lipolysis, inhibition of food intake, delay of gastric emptying, neuroprotection, and pain relief. The antidiabetic and antiobesity properties have led to the development of biologically active and enzymatically stable OXM-based analogs with proposed therapeutic promise for metabolic diseases. Structural modification of OXM was ongoing to enhance its potency and prolong half-life, and several GLP-1/glucagon dual receptor agonist-based therapies are being explored in clinical trials for the treatment of type 2 diabetes mellitus and its complications. In the present article, we provide a brief overview of the physiology of OXM, focusing on its structural-activity relationship and ongoing clinical development.

Metabolic cues impact non-oscillatory intergeniculate leaflet and ventral lateral geniculate nucleus: standard versus high-fat diet comparative study.

The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non-photic (e.g. metabolic and arousal) cues. Both receive information about environmental light from photoreceptors, exhibit infra-slow oscillations (ISO) in vivo, and connect to the master circadian clock. Although current evidence demonstrates that the IGL/VLG communicate metabolic information and are crucial for entrainment of circadian rhythms to time-restricted feeding, their sensitivity to food intake-related peptides has not been investigated yet. We examined the effect of metabolically relevant peptides on the spontaneous activity of IGL/VLG neurons. Using ex vivo and in vivo electrophysiological recordings as well as in situ hybridisation, we tested potential sensitivity of the IGL/VLG to anorexigenic and orexigenic peptides, such as cholecystokinin, glucagon-like peptide 1, oxyntomodulin, peptide YY, orexin A and ghrelin. We explored neuronal responses to these drugs during day and night, and in standard vs. high-fat diet conditions. We found that IGL/VLG neurons responded to all the substances tested, except peptide YY. Moreover, more neurons responded to anorexigenic drugs at night, while a high-fat diet affected the IGL/VLG sensitivity to orexigenic peptides. Interestingly, ISO neurons responded to light and orexin A, but did not respond to the other food intake-related peptides. In contrast, non-ISO cells were activated by metabolic peptides, with only some being responsive to light. Our results show for the first time that peptides involved in the body's energy homeostasis stimulate the thalamus and suggest functional separation of the IGL/VLG cells. KEY POINTS: The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) of the rodent thalamus process various signals and participate in circadian entrainment. In both structures, cells exhibiting infra-slow oscillatory activity as well as non-rhythmically firing neurons being observed. Here, we reveal that only one of these two groups of cells responds to anorexigenic (cholecystokinin, glucagon-like peptide 1 and oxyntomodulin) and orexigenic (ghrelin and orexin A) peptides. Neuronal responses vary depending on the time of day (day vs. night) and on the diet (standard vs. high-fat diet). Additionally, we visualised receptors to the tested peptides in the IGL/VLG using in situ hybridisation. Our results suggest that two electrophysiologically different subpopulations of IGL/VLG neurons are involved in two separate functions: one related to the body's energy homeostasis and one associated with the subcortical visual system.

Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists.

Novel glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have improved efficacy over GLP-1R mono-agonists in treating type 2 diabetes (T2DM) and obesity. Here, we describe the discovery of a novel oxyntomodulin (OXM) based GLP-1R/GCGR dual agonist with potent and balanced potency toward GLP-1R and GCGR. The lead peptide OXM-7 was obtained via stepwise rational design and long-acting modification. In ICR and db/db mice, OXM-7 exhibited prominent acute and long-acting hypoglycemic effects. In diet-induced obesity (DIO) mice, twice-daily administration of OXM-7 produced significant weight loss, normalized lipid metabolism, and improved glucose control. In DIO-nonalcoholic steatohepatitis (NASH) mice, OXM-7 treatment significantly reversed hepatic steatosis, and reduced serum and hepatic lipid levels. These preclinical data suggest the therapeutic potential of OXM-7 as a novel anti-diabetic, anti-steatotic and/or anti-obesity agent.

Development of a selective, sensitive and robust oxyntomodulin dual monoclonal antibody immunoassay.

Background & Aim: Oxyntomodulin (Oxm) is a proglucagon-derived peptide agonist of both the GLP-1 and glucagon receptors and is a key regulator of gastric acid secretion and energy expenditure. Differential processing from proglucagon hinders assay immunoassay selectivity. Method & results: Antibody engineering was used to develop a sandwich immunoassay that selectively measures endogenous Oxm. The pre- and postprandial levels of Oxm from 19 healthy individuals over the course of 2 h were measured. Postprandial increases in Oxm occurred within minutes and levels significantly correlated with those obtained using previously published mass spectrometry assays. Conclusion: This sandwich immunoassay is appropriately sensitive and selective and is also amenable to high-throughput application for the reliable determination of endogenous levels of intact Oxm from human samples.

Factors Affecting the Circulating Levels of Oxyntomodulin in Health and After Acute Pancreatitis.

OBJECTIVES: To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP). METHODS: Blood samples were collected from all participants after an overnight fast and analyzed for 28 biomarkers. Participants also underwent comprehensive body composition analysis on a 3-T magnetic resonance imaging scanner. Regression analyses were done to investigate the associations between oxyntomodulin and the studied factors. RESULTS: The study included 105 individuals who had a primary diagnosis of AP and 58 healthy individuals. Peptide YY (B coefficient, 0.094; 95% confidence interval [95% CI], 0.164-0.123), pancreatic polypeptide (0.048; 95% CI, 0.030-0.066), and leptin (0.394; 95% CI, 0.128-0.661) had significant associations with oxyntomodulin in healthy individuals. Peptide YY was the most prominent factor associated with oxyntomodulin, explaining 60% of its variance in health. Cholecystokinin (0.014; 95% CI, 0.010-0.018), amylin (-0.107; 95% CI, -0.192 to -0.021), and glycated hemoglobin (-0.761; 95% CI, -1.249 to -0.273) had significant associations with oxyntomodulin in individuals after AP. Cholecystokinin was the most prominent factor associated with oxyntomodulin, explaining 44% of its variance after AP. CONCLUSIONS: Factors affecting the circulating levels of oxyntomodulin are different in health and after AP. These insights will enable the determination of populations that benefit from oxyntomodulin therapeutics in the future.

BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy.

OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. METHODS: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. RESULTS: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. CONCLUSIONS: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.

Circulating levels of five proglucagon-derived peptides in response to intravenous or oral glucose or lipids and to a mixed-meal in subjects with normal weight, overweight, and obesity.

AIMS: Proglucagon-derived peptides (PGDPs) secreted by the gut and pancreas play a major role in metabolism. We measured concentrations of five PGDPs in response to per os (PO) or intravenous (IV) glucose or lipid intake and a mixed meal test (MMT) consumed by subjects with normal weight, overweight or obesity. MATERIALS AND METHODS: GLP-1, oxyntomodulin and glicentin (gut-secreted PGDPs) and glucagon and MPGF (pancreas-secreted PGDPs) were assessed in: (a) 32 subjects receiving PO or IV glucose, lipids or water over 6 h, (b) 33 subjects with normal weight, overweight or obesity who consumed a MMT. RESULTS: (a) GLP-1, oxyntomodulin, glicentin and glucagon levels increase more profoundly and persistently after lipids PO (2.5  g/kg) than glucose PO (2.5  g/kg) or IV lipids (Intralipid/Liposyn II 20% at 0.35 ml/kg/h and Intralipid/Liposyn II 20% at 0.83  ml/kg/h for 6 h) or IV glucose (10% glucose at 3.6 ml/kg/h for 6 h). Oxyntomodulin and glicentin increased more than GLP-1 in response to lipids PO. MPGF levels decrease in response to glucose PO or IV indicating a shift towards preferential production of gut-secreted peptides. (b) Fasting and postprandial areas under the curve (AUCs) after MMT of GLP-1, MPGF and glucagon levels correlated positively with BMI. The fasting levels of glucagon and MPGF were elevated in obesity and remained elevated after the MMT. CONCLUSION: Circulating levels of PGDPs are differentially regulated by body weight, the type of macronutrients administered and the respective route of administration. Mechanistic studies are needed to define the exact mechanisms underlying this regulation. CLINICAL TRIAL REGISTRATION: Study 1 has the NCT01520454 and the NCT04888325 number in ClinicalTrials.gov. Study 2 has the number NCT01495754 in ClinicalTrials.gov.

Methods paper: Performance characteristics of novel assays for circulating levels of proglucagon-derived peptides and validation in a placebo controlled cross-over randomized clinical trial.

BACKGROUND: The measurement of proglucagon-derived peptides (PGDPs) is a challenging task mainly due to major overlaps in their molecular sequence in addition to their low circulating levels. Here, we present the technical characteristics of novel ELISA assays measuring C-peptide and all six PGDPs including, for the first time, major proglucagon fragment (MPGF), and we validate them by performing a pilot in vivo cross-over randomized clinical trial on whether coffee consumption may affect levels of circulating PGDPs. METHODS: The performance and technical characteristics of novel ELISA assays from Ansh measuring GLP-1, GLP-2, oxyntomodulin, glicentin, glucagon, MPGF and C-peptide were first evaluated in vitro in procured samples from a commercial vendor as well as in deidentified human samples from three previously performed clinical studies. Their performance was further evaluated in vivo in the context of a cross-over randomized controlled trial, in which 33 subjects consumed in random order and together with a standardized meal, 200 ml of either (a) instant coffee with 3 mg/kg caffeine, or (b) instant coffee with 6 mg/kg caffeine, (c) or water. RESULTS: All assays demonstrated high accuracy (spike and recovery and average linearity recovery ±15%), precision (inter-assay CV ≤ 6.4%), specificity (no significant cross-reactivities) and they were sensitive in low concentrations. Measurements of glicentin in archived random human samples using the Ansh assay correlated strongly with the glicentin measurements of Mercodia assay (r = 0.968) and of GLP-1 modestly with Millipore GLP-1 assay (r = 0.440). Oxyntomodulin, glicentin and glucagon concentrations were 2-5 fold higher in plasma compared to serum and serum concentrations correlated modestly (for oxyntomodulin and glicentin) or poorly (for glucagon) with the plasma concentrations. The evaluated assays detected a postprandial increase of gut-secreted PGDPs (GLP-1, GLP-2, oxyntomodulin and glicentin) and a postprandial decrease of pancreas-secreted PGDPs (glucagon, MPGF) in response to consuming coffee in comparison to consuming water with breakfast (enter here composition of breakfast). Only coffee consumption at the high dose alter levels of gut-secreted PGDPs and both at low and high dose to lower levels of pancreas-secreted PGDPs compared to water consumption during breakfast. CONCLUSION: Accurate, precise and specific measurement of six PGDPs is possible with novel assays. A randomized controlled trial demonstrated in vivo utility of those assays and supports the notion that coffee may exert part of its beneficial effects on glucose homeostasis in the short term through the regulation of PGDPs.

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation.

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

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.

Peptides in the regulation of glucagon secretion.

Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist.

OBJECTIVE: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and ß-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss. RESULTS: Ligand-specific reductions in ß-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and ß-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS: Diminishing ß-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake.

The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids.

We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.

Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward- and attention-related brain centres in response to visual food cues in adults with obesity: A cross-sectional functional MRI study.

Postprandial increases in gastrointestinal hormones are associated with reduced energy intake, partially through direct effects on the brain. However, it remains unknown whether the fasting levels of gastrointestinal hormones are associated with altered brain activity in response to visual food stimuli. We therefore performed a whole-brain regression cross-sectional analysis to assess the association between fasting brain activations according to functional magnetic resonance imaging, performed during viewing of highly desirable versus less desirable food images, with fasting levels of five gastrointestinal hormones (glucagon-like peptide [GLP]-1, GLP-2, oxyntomodulin, glicentin and gastric inhibitory polypeptide [GIP]) in 36 subjects with obesity. We observed that fasting blood levels of GIP were inversely associated with the activation of attention-related areas (visual cortices of the occipital lobe, parietal lobe) and of oxyntomodulin and glicentin with reward-related areas (insula, putamen, caudate for both, and additionally orbitofrontal cortex for glicentin) and the hypothalamus when viewing highly desirable as compared to less desirable food images. Future studies are needed to confirm whether fasting levels of oxyntomodulin, glicentin and GIP are associated with the activation of brain areas involved in appetite regulation and with energy intake in people with obesity.