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.

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.

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.

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.

Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors.

Metabolic diseases such as obesity, diabetes, and their comorbidities have converged as one of the most serious health concerns on a global scale. Selective glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists are one of the major therapeutics for type 2 diabetes and obesity. Polypharmacological approaches that enable modulation of multiple metabolic targets in a single drug have emerged as a potential avenue to improve therapeutic outcomes. Among numerous peptides under development are those targeting the GLP-1R and either the glucagon receptor (GCGR), glucose-dependent insulinotropic peptide receptor (GIPR) or all 3 receptors, as dual- or tri- peptide agonists. Despite many of them entering into clinical trials, current development has been based on only a limited understanding of the spectrum of potential pharmacological properties of these ligands beyond binding selectivity. In the present study, we examined the potential for agonists that target both GLP-1R and GCGR to exhibit biased agonism, comparing activity across proximal activation of Gs protein, cAMP accumulation, pERK1/2 and ß-arrestin recruitment. Three distinct dual agonists that have different relative cAMP production potency for GLP-1R versus GCGR, "peptide 15", MEDI0382 and SAR425899, and one triagonist of the GLP-1R, GCGR and GIPR were examined. We demonstrated that all novel peptides have distinct biased agonism profiles relative to either of the cognate agonists of the receptors, and to each other. This is an important feature of the pharmacology of this drug class that needs to be considered alongside selectivity, bioavailability and pharmacokinetics for rational optimization of new therapeutics.

Oxyntomodulin attenuates TNF­α induced neuropathic pain by inhibiting the activation of the NF­κB pathway.

Neuropathic pain is rarely diagnosed. Oxyntomodulin is peripherally and centrally distributed; however, the potential mechanisms underlying the effects of oxyntomodulin in attenuating nociception remain unclear; thus, we aimed to explore them in the present study. A neuropathic pain model in male C57BL/6 mice was induced by intrathecal injection of tumor necrosis factor­α (TNF­α), and the duration of nociceptive behavioral responses was measured with a stop­watch timer within 30 min. Western blotting was used to explore the protein levels of ionized calcium binding adaptor molecule­1 (IBA1), nuclear factor­κB (NF­κB) phosphorylated­p65, interleukin (IL)­6 and IL­1ß. We performed reverse transcription­quantitative polymerase chain reaction and ELISA were performed to determine the mRNA and protein expression levels of IL­6 and IL­1ß, respectively. An MTT assay was conducted to detect BV2 cell viability. Oxyntomodulin was observed to attenuate TNF­α­induced pain hypersensitivity in mice, as well as the expression of IBA1, NF­κB p­p65, IL­6 and IL­1ß in the spinal cord. Oxyntomodulin exhibited no cytotoxicity on BV2 cells, and attenuated TNF­α­induced IL­6 and IL­1ß production and release in BV2 cells and culture medium, respectively. Collectively, we proposed oxyntomodulin to attenuate TNF­α induced neuropathic pain associated with the release of glial cytokines IL­6 and IL­1ß via inhibiting the activation of the NF­κB pathway.

Cellular and sub-cellular localisation of oxyntomodulin-like immunoreactivity in enteroendocrine cells of human, mouse, pig and rat.

We use a monoclonal antibody against the C-terminal of oxyntomodulin (OXM) to investigate enteroendocrine cells (EEC) in mouse, rat, human and pig. This antibody has cross-reactivity with the OXM precursor, glicentin (Gli) but does not recognise glucagon. The antibody stained EEC in the jejunum and colon of each species. We compared OXM/Gli immunoreactivity with that revealed by antibodies against structurally related peptides, GLP-1 and glucagon and against GIP and PYY that are predicted to be in some EEC that express OXM/Gli. We used super-resolution to locate immunoreactive vesicles. In the pancreas, OXM/Gli was in glucagon cells but was located in separate storage vesicles to glucagon. In jejunal EEC, OXM/Gli and GIP were in many of the same cells but often in separate vesicles, whereas PYY and OXM/Gli were commonly colocalised in the same storage vesicles of colonic EEC. When binding of anti-GLP-1 to the structurally related GIP was removed by absorption with GIP peptide, GLP-1 and OXM/Gli immunoreactivities were contained in the same population of EEC in the intestine. We conclude that anti-OXM/Gli is a more reliable marker than anti-GLP-1 for EEC expressing preproglucagon products. Storage vesicles that were immunoreactive for OXM/Gli were almost always immunoreactive for GLP-1. OXM concentrations, measured by ELISA, were highest in the distal ileum and colon. Lesser concentrations were found in more proximal parts of small intestine and pancreas. Very little was in the stomach. In EEC containing GIP and OXM/Gli, these hormones are packaged in different secretory vesicles. Separate packaging also occurred for OXM and glucagon, whereas OXM/Gli and PYY and OXM/Gli and GLP-1 were commonly contained together in secretory vesicles.

Oxyntomodulin: Actions and role in diabetes.

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.

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance.

The gastrointestinal tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural, and nutrient signals emanating from the gastrointestinal tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacologic and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing body weight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy. However, the recent finding of sustained weight reduction in response to systemic administration of a long-acting analog of the gut-hormone glucagon-like peptide-1 highlights the therapeutic potential of gut-derived signals acting via nonphysiologic mechanisms. Thus, we also review therapeutics strategies being utilized or developed to leverage gastrointestinal signals in order to treat obesity.

Physiological and pathophysiological aspects of incretin hormones and glucagon.

Infusion of oxyntomodulin and the separate and combined infusion of GLP-1 and glucagon inhibited food intake similarly in healthy individuals, with no superior effect of combining GLP-1 and glucagon. We confirm the inhibitory effects of oxyntomodulin and GLP-1, respectively, on GE and appetite scores observed previously, but by adding glucagon to the infusion of GLP-1 we found no additive effects. Unexpectedly, glucagon alone had no effect on GE and appetite scores, but inhibited food intake to the same extent as oxyntomodulin, GLP-1 and GLP-1 + glucagon. Both the GLP-1, oxyntomodulin and GLP-1 + glucagon infusions appeared to increase O2 compared to saline but this observation is most likely confounded by a residual meal-induced thermogenesis because the calorimetry was performed relatively soon after the paracetamol peak indicating that a considerable volume still resided in the stomach and a high rate of nutrient absorption probably was still going on compared to the saline infusion. Flint et al previously concluded from a protocol very similar to ours using GLP-1 infusions, that the observed increases in energy expenditure most likely were linked to the meal. In contrast, we observed no significant changes in O2 from baseline in any of the experiments in our study. The lack of a clear effect on O2 is in contrast to recently reported findings regarding infusions of glucagon and GLP-1. But the dose of glucagon used in that particular study was more than 15-fold higher than ours and associated with large changes in glucose and insulin levels. Such levels are likely to influence REE and offer an explanation of the reported additive effect of combinations of GLP-1 and glucagon. Our conclusion is consistent with recent findings showing no increases after short-term native GLP-1 infusions. Long-term treatment with the GLP-1 analogue liraglutide using 24 h chamber calorimetry has so far shown no differences in energy expenditure following the treatment. Surprisingly, the infusion of glucagon did not change gastric emptying. This finding is controversial since glucagon previously has been used to inhibit bowel motility. However, the doses used to inhibit bowel motility were more than 3,000-fold higher than the dose used in the present study and as mentioned above, such doses might activate the GLP-1 receptor pathway. Interestingly, the glucagon infusion did result in decreased food intake to the same extent as the other peptide infusions despite having no impact on gastric emptying and appetite scores. We found a mean 180 kcal (120 g) difference in food intake following infusions of all the peptides compared to saline. This would roughly sum up to a body weight loss of 402 g of fat per week, which is in the range of what previously has been found in overweight and obese humans with the injection of oxyntomodulin.

Peptide-based GLP-1/glucagon co-agonists: A double-edged sword to combat diabesity.

Diabesity is a new term for obesity-dependent diabetes, which is also associated with cardiovascular and other comorbidities with rising epidemic. Traditional treatments (sulfonylureas and thiazolidinediones) of diabetes are associated with weight gain, except metformin. Newer agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Sodium glucose co-transporter 2 inhibitors (SGLT2i) are causing a modest weight reduction, whereas dipeptidyl peptidase-4 inhibitors (DPP-4i) are weight neutral. Oxyntomodulin, a native GLP-1/glucagon receptor agonist produced a superior weight loss and antihyperglycemic effects in obese mice and humans. Recent findings with synthetic dual GLP-1/glucagon receptor agonists have shown a good weight loss and antihyperglycemic profile in diet-induced obese (DIO) mice. Targeting combinations of GLP-1 receptor and glucagon receptor simultaneously with a single peptide may be the better strategy to achieve marked weight loss and considerable glycemic control in diabesity. Cardiovascular safety is very important with new antidiabetic agents due to rosiglitazone controversy. Current on-going clinical trials will clarify the cardiovascular effects of incretin-based therapies in near future. Based on current knowledge and rapid progress in the field, there is a strong possibility that the GLP-1/glucagon receptor co-agonists will likely be the new therapeutic treatment for diabesity for decades to come.

The biology of glucagon and the consequences of hyperglucagonemia.

The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, hyperglucagonemia, may contribute to diabetes. However, hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.

The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

The intestinal distribution pattern of appetite- and glucose regulatory peptides in mice, rats and pigs.

BACKGROUND: Mice, rats, and pigs are the three most used animal models when studying gastrointestinal peptide hormones; however their distribution from the duodenum to the distal colon has not been characterized systematically across mice, rats and pigs. We therefore performed a comparative distribution analysis of the tissue content of the major appetite- and glucose regulatory peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 (GLP-2), oxyntomodulin/glicentin, neurotensin, and peptide YY (PYY) from the duodenum to distal colon in mice (n = 9), rats (n = 9) and pigs (n = 8), using validated radioimmunoassays. RESULTS: GLP-1, GLP-2 and oxyntomodulin/glicentin show similar patterns of distribution within the respective species, but for rats and pigs the highest levels were found in the distal small intestine, whereas for the mouse the highest level was found in the distal colon. In rats and pigs, neurotensin was predominantly detected in mid and lower part of the small intestine, while the mouse showed the highest levels in the distal small intestine. In contrast, the distribution of GIP was restricted to the proximal small intestine in all three species. Most surprisingly, in the pig PYY was found in large amounts in the proximal part of the small intestine whereas both rats and mice had undetectable levels until the distal small intestine. CONCLUSIONS: In summary, the distribution patterns of extractable GIP, GLP-1, GLP-2, oxyntomodulin/glicentin, neurotensin are preserved across species whereas PYY distribution showed marked differences.

Do glucagonomas always produce glucagon?

Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.

Gastrointestinal hormones and their role in obesity.

PURPOSE OF REVIEW: Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery. This article examines in detail three of these gut hormones: peptide YY, oxyntomodulin and pancreatic polypeptide, and reviews how recent developments may offer new targets for therapy. RECENT FINDINGS: Both the free fatty acid 2 and the melanocortin 4 receptors have been discovered to regulate peptide YY and glucagon-like peptide-1 secretion, and drugs targeting these may represent new antiobesity therapies. Dual agonism of glucagon-like peptide-1 and glucagon receptors, for example with oxyntomodulin, has synergistic effects in reducing appetite and increasing energy expenditure. Plasma pancreatic polypeptide concentration correlates with visceral adiposity, and may serve as a biomarker for metabolic syndrome. SUMMARY: Gut hormones continue to show promise on an individual basis as anti-obesity treatments, but combination therapies are needed to achieve beneficial effects comparable to bariatric surgery. Innovative pathways for stimulating native gut hormone secretion may well provide an alternative method for weight loss without necessitating the administration of gut hormone analogues via injection.

Oxyntomodulin regulates resetting of the liver circadian clock by food.

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.

Abnormal rectal endocrine cells in patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. In a previous study the total number of endocrine cells in the rectum of IBS patients, as detected by chromogranin A, did not differ from that of healthy controls. While the total endocrine cell content of the rectum appears to be unchanged in IBS patients, changes in particular endocrine cells cannot be excluded. This study was undertaken, therefore, to investigate the cell density of different rectal endocrine cell types in (IBS) patients. Fifty patients with IBS (41 females and 9 males) were included in the study. Thirty patients had diarrhoea (IBS-D) and 20 had constipation (IBS-C) as the predominant symptom. Twenty-seven subjects were included as controls (19 females and 8 males). Rectal biopsy specimens were immunostained using the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), and oxyntomodulin and somatostatin cells. The cell densities were quantified by computerised image analysis. The serotonin cell density did not differ significantly, although a type II statistical error cannot be excluded, due to the small size of the sample. The densities of PYY and Oxyntomodulin cells were significantly lower and that of somatostatin were significantly higher in IBS patients than controls. These abnormalities were observed in both IBS-D and IBS-C patients. The abnormalities in the endocrine cells observed in this study in the rectum differed considerably from those seen in the colon of IBS patients. This indicates that caution in using the rectum to represent the large intestine in these patients. These abnormalities could be primary (genetic) or secondary to changes in the gut hormones found in other segments of the gut and/or other pathological processes. Although the-cause-and effect relationship of the abnormalities found in rectal endocrine cells is difficult to elucidate, they might contribute to the symptoms associated with IBS. The densities of PYY and somatostatin cells are potential biomarkers with good sensitivity and specificity for the diagnosis of IBS.

Gastrointestinal hormones and bariatric surgery-induced weight loss.

UNLABELLED: Obesity continues to be a major public health problem in the United States and worldwide. While recent statistics have demonstrated that obesity rates have begun to plateau, more severe classes of obesity are accelerating at a faster pace with important implications in regards to treatment. Bariatric surgery has a profound and durable effect on weight loss, being to date one of the most successful interventions for obesity. OBJECTIVE: To provide updates to the possible role of gut hormones in post bariatric surgery weight loss and weight loss maintenance. DESIGN AND METHODS: The current review examines the changes in gastro-intestinal hormones with bariatric surgery and the potential mechanisms by which these changes could result in decreased weight and adiposity. RESULTS: The mechanism by which bariatric surgery results in body weight changes is incompletely elucidated, but it clearly goes beyond caloric restriction and malabsorption. CONCLUSION: Changes in gastro-intestinal hormones, including increases in GLP-1, PYY, and oxyntomodulin, decreases in GIP and ghrelin, or the combined action of all these hormones might play a role in induction and long-term maintenance of weight loss.

Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis.

Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.