scholarly journals Targeting the Gut in Obesity: Signals from the Inner Surface

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 39
Author(s):  
Natalia Petersen ◽  
Thomas U. Greiner ◽  
Lola Torz ◽  
Angie Bookout ◽  
Marina Kjærgaard Gerstenberg ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Gut Hormones ◽  
Energy Balance Equation ◽  
Enteroendocrine Cells ◽  
Therapeutic Interventions ◽  
Microbial Metabolites ◽  
Dipeptidyl Peptidase 4 ◽  
Gut Hormone ◽  
Glucagon Like Peptide 1 ◽  
The Brain

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve. Intestinally derived messengers are manifold and include absorbed nutrients, microbial metabolites, gut hormones and other enterokines, collectively comprising a fine-tuned signalling system to the brain. After a meal, nutrients directly interact with appetite-inhibiting areas of the brain and induce satiety. However, overall feeding behaviour also depends on secretion of gut hormones produced by highly specialized and sensitive enteroendocrine cells. Moreover, circulating microbial metabolites and their interactions with enteroendocrine cells further contribute to the regulation of feeding patterns. Current therapies exploiting the appetite-regulating properties of the gut are based on chemically modified versions of the gut hormone, glucagon-like peptide-1 (GLP-1) or on inhibitors of the primary GLP-1 inactivating enzyme, dipeptidyl peptidase-4 (DPP-4). The effectiveness of these approaches shows that that the gut is a promising target for therapeutic interventions to achieve significant weigh loss. We believe that increasing understanding of the functionality of the intestinal epithelium and new delivery systems will help develop selective and safe gut-based therapeutic strategies for improved obesity treatment in the future. Here, we provide an overview of the major homeostatic appetite-regulating signals generated by the intestinal epithelial cells and how these signals may be harnessed to treat obesity by pharmacological means.

scholarly journals Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 883
Author(s):  
Van B. Lu ◽  
Fiona M. Gribble ◽  
Frank Reimann
Keyword(s):  
Gastrointestinal Tract ◽  
Hormone Secretion ◽  
Gut Hormones ◽  
Nutrient Sensing ◽  
Enteroendocrine Cells ◽  
Cellular Mechanisms ◽  
Channel Modulation ◽  
Gut Hormone ◽  
Nutrient Utilisation ◽  
Glucagon Like Peptide 1

The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.

scholarly journals Neurotensin Is Coexpressed, Coreleased, and Acts Together With GLP-1 and PYY in Enteroendocrine Control of Metabolism

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 176-194 ◽  
Author(s):  
Kaare V. Grunddal ◽  
Cecilia F. Ratner ◽  
Berit Svendsen ◽  
Felix Sommer ◽  
Maja S. Engelstoft ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Secretory Granules ◽  
Gut Hormones ◽  
Distal Small Intestine ◽  
Cell Ablation ◽  
Target Organs ◽  
Gut Hormone ◽  
Toxin Receptor ◽  
Functional Consequences ◽  
Glucagon Like Peptide 1

Abstract The 2 gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are well known to be coexpressed, costored, and released together to coact in the control of key metabolic target organs. However, recently, it became clear that several other gut hormones can be coexpressed in the intestinal-specific lineage of enteroendocrine cells. Here, we focus on the anatomical and functional consequences of the coexpression of neurotensin with GLP-1 and PYY in the distal small intestine. Fluorescence-activated cell sorting analysis, laser capture, and triple staining demonstrated that GLP-1 cells in the crypts become increasingly multihormonal, ie, coexpressing PYY and neurotensin as they move up the villus. Proglucagon promoter and pertussis toxin receptor-driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY- and neurotensin-positive cells. High-resolution confocal fluorescence microscopy demonstrated that neurotensin is stored in secretory granules distinct from GLP-1 and PYY storing granules. Nevertheless, the 3 peptides were cosecreted from both perfused small intestines and colonic crypt cultures in response to a series of metabolite, neuropeptide, and hormonal stimuli. Importantly, neurotensin acts synergistically, ie, more than additively together with GLP-1 and PYY to decrease palatable food intake and inhibit gastric emptying, but affects glucose homeostasis in a more complex manner. Thus, neurotensin is a major gut hormone deeply integrated with GLP-1 and PYY, which should be taken into account when exploiting the enteroendocrine regulation of metabolism pharmacologically.

DIFFERENTIAL EFFECTS OF BILE ACIDS ON THE POST-PRANDIAL SECRETION OF GUT HORMONES: a randomised crossover study

2021 ◽  
Author(s):  
Emma Rose McGlone ◽  
Khalefah Malallah ◽  
Joyceline Cuenco ◽  
Nicolai J. Wewer Albrechtsen ◽  
Jens J. Holst ◽  
...  
Keyword(s):  
Bile Acids ◽  
Peptide Yy ◽  
Gut Hormones ◽  
Mixed Meal ◽  
Gut Hormone ◽  
Mixed Meal Test ◽  
Hormone Responses ◽  
Glucagon Like Peptide 1 ◽  
Fibroblast Growth Factor 19 ◽  
Insulinotropic Peptide

AIMS Bile acids (BA) regulate post-prandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The post-prandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effect of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on post-prandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon and ghrelin. METHODS Twelve healthy volunteers underwent a mixed meal test 60 minutes after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg) or no BA in a randomised cross-over study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin and fibroblast growth factor 19 were measured prior to BA administration at -60, 0 (just prior to mixed meal) and 15, 30, 60, 120, 180 and 240 minutes after the meal. RESULTS UDCA and CDCA provoked differential gut hormone responses: UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced post-prandial secretion of GIP, with an associated reduction in post-prandial insulin secretion. CONCLUSIONS Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmedin obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.

scholarly journals Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study

2015 ◽  
Vol 113 (4) ◽  
pp. 574-584 ◽  
Author(s):  
H. Frances J. Bligh ◽  
Ian F. Godsland ◽  
Gary Frost ◽  
Karl J. Hunter ◽  
Peter Murray ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Blood Glucose Control ◽  
Gut Hormones ◽  
Acute Effects ◽  
Randomised Study ◽  
Satiety Response ◽  
Gut Hormone ◽  
Palaeolithic Diet ◽  
Glucagon Like Peptide 1 ◽  
Few Data

There is evidence for health benefits from ‘Palaeolithic’ diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

scholarly journals Combination gut hormones: prospects and questions for the future of obesity and diabetes therapy

2020 ◽  
Vol 246 (3) ◽  
pp. R65-R74 ◽  
Author(s):  
Bernard Khoo ◽  
Tricia Mei-Mei Tan
Keyword(s):  
Peptide Yy ◽  
Gut Hormones ◽  
Clinical Results ◽  
Therapeutic Effects ◽  
Physiological Basis ◽  
Obesity And Diabetes ◽  
Gut Hormone ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity ◽  
Insulinotropic Peptide

Obesity represents an important public health challenge for the twenty-first century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy, and as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1’s therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.

scholarly journals Mechanisms controlling hormone secretion in human gut and its relevance to metabolism

2020 ◽  
Vol 244 (1) ◽  
pp. R1-R15 ◽  
Author(s):  
Alyce M Martin ◽  
Emily W Sun ◽  
Damien J Keating
Keyword(s):  
Hormone Secretion ◽  
Enteroendocrine Cells ◽  
Microbial Metabolites ◽  
Human Gut ◽  
Glucose Lowering ◽  
Endocrine Organ ◽  
Metabolic Functions ◽  
Gut Epithelium ◽  
Gut Hormone ◽  
Regulation Of Metabolism

The homoeostatic regulation of metabolism is highly complex and involves multiple inputs from both the nervous and endocrine systems. The gut is the largest endocrine organ in our body and synthesises and secretes over 20 different hormones from enteroendocrine cells that are dispersed throughout the gut epithelium. These hormones include GLP-1, PYY, GIP, serotonin, and CCK, each of which play pivotal roles in maintaining energy balance and glucose homeostasis. Some are now the basis of several clinically used glucose-lowering and weight loss therapies. The environment in which these enteroendocrine cells exist is also complex, as they are exposed to numerous physiological inputs including ingested nutrients, circulating factors and metabolites produced from neighbouring gut microbiome. In this review, we examine the diverse means by which gut-derived hormones carry out their metabolic functions through their interactions with different metabolically important organs including the liver, pancreas, adipose tissue and brain. Furthermore, we discuss how nutrients and microbial metabolites affect gut hormone secretion and the mechanisms underlying these interactions.

scholarly journals Dissociable hormonal profiles for psychopathology and stress in anorexia and bulimia nervosa

2020 ◽  
pp. 1-11 ◽  
Author(s):  
Margaret L. Westwater ◽  
Flavia Mancini ◽  
Jane Shapleske ◽  
Jaco Serfontein ◽  
Monique Ernst ◽  
...  
Keyword(s):  
Bulimia Nervosa ◽  
Acute Stress ◽  
Gut Hormones ◽  
Metabolic Dysfunction ◽  
Cortisol Reactivity ◽  
Psychological States ◽  
Gut Hormone ◽  
Ad Libitum ◽  
Glucagon Like Peptide 1 ◽  
Acyl Ghrelin

Abstract Background Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric conditions, in which both psychological and metabolic factors have been implicated. Critically, the experience of stress can precipitate loss-of-control eating in both conditions, suggesting an interplay between mental state and metabolic signaling. However, associations between psychological states, symptoms and metabolic processes in AN and BN have not been examined. Methods Eighty-five women (n = 22 AN binge/purge subtype, n = 33 BN, n = 30 controls) underwent remote salivary cortisol sampling and a 2-day, inpatient study session to examine the effect of stress on cortisol, gut hormones [acyl-ghrelin, peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1] and food consumption. Participants were randomized to either an acute stress induction or control task on each day, and plasma hormones were serially measured before a naturalistic, ad libitum meal. Results Cortisol-awakening response was augmented in AN but not in BN relative to controls, with body mass index explaining the most variance in post-awakening cortisol (36%). Acute stress increased acyl-ghrelin and PYY in AN compared to controls; however, stress did not alter gut hormone profiles in BN. Instead, a group-by-stress interaction showed nominally reduced cortisol reactivity in BN, but not in AN, compared to controls. Ad libitum consumption was lower in both patient groups and unaffected by stress. Conclusions Findings extend previous reports of metabolic dysfunction in binge-eating disorders, identifying unique associations across disorders and under stress. Moreover, we observed disrupted homeostatic signaling in AN following psychological stress, which may explain, in part, the maintenance of dysregulated eating in this serious illness.

GLP-1: A Mediator of the Beneficial Metabolic Effects of Bariatric Surgery?

Physiology ◽  
2015 ◽  
Vol 30 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Sean Manning ◽  
Andrea Pucci ◽  
Rachel L. Batterham
Keyword(s):  
Bariatric Surgery ◽  
Gastric Bypass ◽  
Sleeve Gastrectomy ◽  
Gut Hormones ◽  
Metabolic Effects ◽  
Physiological Changes ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

There has been increasing interest in the role that gut hormones may play in contributing to the physiological changes produced by certain bariatric procedures, such as Roux-en-Y gastric bypass and sleeve gastrectomy. Here, we review the evidence implicating one such gut hormone, glucagon-like peptide-1, as a mediator of the metabolic benefits of these two procedures.

scholarly journals Short-term treatment with olanzapine does not modulate gut hormone secretion: olanzapine disintegrating versus standard tablets

2010 ◽  
Vol 162 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Solrun Vidarsdottir ◽  
Ferdinand Roelfsema ◽  
Trea Streefland ◽  
Jens J Holst ◽  
Jens F Rehfeld ◽  
...  
Keyword(s):  
Weight Gain ◽  
Peptide Yy ◽  
Hormone Secretion ◽  
Gut Hormones ◽  
Term Treatment ◽  
Short Term ◽  
Short Term Treatment ◽  
Healthy Men ◽  
Gut Hormone ◽  
Glucagon Like Peptide 1

BackgroundTreatment with olanzapine (atypical antipsychotic drug) is frequently associated with various metabolic anomalies, including obesity, dyslipidemia, and diabetes mellitus. Recent data suggest that olanzapine orally disintegrating tablets (ODT), which dissolve instantaneously in the mouth, might cause less weight gain than olanzapine standard oral tablets (OST).Design and methodsTen healthy men received olanzapine ODT (10 mg o.d., 8 days), olanzapine OST (10 mg o.d., 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, blood samples were taken for measurement of pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin (CCK) concentrations.ResultsWith the exception of pre- and postprandial concentration of ghrelin at dinner and preprandial CCK concentrations at breakfast, which were all slightly increased (respectivelyP=0.048,P=0.034 andP=0.042), olanzapine did not affect gut hormone concentrations. Thus, olanzapine ODT and OST had similar effects on gut hormone secretion.ConclusionShort-term treatment with olanzapine does not have major impact on the plasma concentration of gut hormones we measured in healthy men. Moreover, despite pharmacological difference, gut hormone concentrations are similar during treatment with olanzapine ODT and OST. The capacity of olanzapine to induce weight gain and diabetes is unlikely to be caused by modulation of the secretion of gut hormones measured here. We cannot exclude the possibility that olanzapine's impact on other gut hormones, to impair insulin sensitivity and stimulate weight gain, exists.

scholarly journals Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans

2014 ◽  
Vol 306 (7) ◽  
pp. G622-G630 ◽  
Author(s):  
Rune E. Kuhre ◽  
Fiona M. Gribble ◽  
Bolette Hartmann ◽  
Frank Reimann ◽  
Johanne A. Windeløv ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Hormone Secretion ◽  
Gut Hormones ◽  
Glucagon Secretion ◽  
Healthy Humans ◽  
Murine Cell Line ◽  
Gut Hormone ◽  
Glucagon Like Peptide 1 ◽  
Cell Depolarization ◽  
Gip Release

Nutrients often stimulate gut hormone secretion, but the effects of fructose are incompletely understood. We studied the effects of fructose on a number of gut hormones with particular focus on glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In healthy humans, fructose intake caused a rise in blood glucose and plasma insulin and GLP-1, albeit to a lower degree than isocaloric glucose. Cholecystokinin secretion was stimulated similarly by both carbohydrates, but neither peptide YY3–36nor glucagon secretion was affected by either treatment. Remarkably, while glucose potently stimulated GIP release, fructose was without effect. Similar patterns were found in the mouse and rat, with both fructose and glucose stimulating GLP-1 secretion, whereas only glucose caused GIP secretion. In GLUTag cells, a murine cell line used as model for L cells, fructose was metabolized and stimulated GLP-1 secretion dose-dependently (EC50= 0.155 mM) by ATP-sensitive potassium channel closure and cell depolarization. Because fructose elicits GLP-1 secretion without simultaneous release of glucagonotropic GIP, the pathways underlying fructose-stimulated GLP-1 release might be useful targets for type 2 diabetes mellitus and obesity drug development.

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