Differential changes in appetite hormones post-prandially based on menstrual cycle phase and oral contraceptive use: A preliminary study.

This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.

Neurocircuitry underlying the actions of glucagon-like peptide 1 and peptide YY3-36 in the suppression of food, drug-seeking, and anxiogenesis.

Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY3-36 (PYY3-36), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY3-36 when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY3-36 on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY3-36 may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.

Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion.

Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.

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.

Gut motility and hormone changes after bariatric procedures.

PURPOSE OF REVIEW: Metabolic and bariatric surgery (MBS) and endoscopic bariatric therapies (EBT) are being increasingly utilized for the management of obesity. They work through multiple mechanisms, including restriction, malabsorption, and changes in the gastrointestinal hormonal and motility. RECENT FINDINGS: Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) cause decrease in leptin, increase in GLP-1 and PYY, and variable changes in ghrelin (generally thought to decrease). RYGB and LSG lead to rapid gastric emptying, increase in small bowel motility, and possible decrease in colonic motility. Endoscopic sleeve gastroplasty (ESG) causes decrease in leptin and increase in GLP-1, ghrelin, and PYY; and delayed gastric motility. SUMMARY: Understanding mechanisms of action for MBS and EBT is critical for optimal care of patients and will help in further refinement of these interventions.

Intestinal Acyl-CoA synthetase 5 (ACSL5) deficiency potentiates postprandial GLP-1 & PYY secretion, reduces food intake, and protects against diet-induced obesity.

OBJECTIVE: In the small intestine, the products of digestion of dietary triacylglycerol (TAG), fatty acids (FA) and monoacylglycerol, are taken up by absorptive cells, enterocytes, for systemic energy delivery. These digestion products can also bind receptors on endocrine cells to stimulate the release of hormones capable of influencing systemic energy metabolism. The initial phase of intestinal FA absorption involves the acylation of FAs to acyl-CoA by the acyl-CoA long chain synthetase (ACSL) enzymes. ACSL5 is abundantly expressed in the small intestinal epithelium where it is the major ACSL isoform, contributing approximately 80% of total ACSL activity. In mice with whole body deficiency of ACSL5, the rate of dietary fat absorption is reduced and energy expenditure is increased. However, the mechanisms by which intestinal ACSL5 contributes to intestinal FA metabolism, enteroendocrine signaling, and regulation of energy expenditure remain undefined. Here, we test the hypothesis that intestinal ACSL5 regulates energy metabolism by influencing dietary fat absorption and enteroendocrine signaling. METHODS: To explore the role of intestinal ACSL5 in energy balance and intestinal dietary fat absorption, a novel mouse model of intestine specific ACSL5 deficiency (ACSL5IKO) was generated by breeding ACSL5 floxed (ACSL5loxP/loxP) to mice harboring the tamoxifen inducible, villin-Cre recombinase. ACSL5IKO and control, ACSL5loxP/loxP mice were fed chow (low in fat) or a 60% high fat diet (HFD), and metabolic phenotyping was performed including, body weight, body composition, insulin and glucose tolerance tests, energy expenditure, physical activity, and food intake studies. Pair-feeding studies were performed to determine the role of food intake in regulating development of obesity. Studies of dietary fat absorption, fecal lipid excretion, intestinal mucosal FA content, and circulating levels of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) in response to a TAG challenge were performed. Treatment with a GLP-1 receptor antagonist was performed to determine the contribution of GLP-1 to acute regulation of food intake. RESULTS: We found that ACSL5IKO mice experienced rapid and sustained protection from body weight and fat mass accumulation during HFD feeding. While intestine specific deficiency of ACSL5 delayed gastric emptying and reduced dietary fat secretion, it did not result in increased excretion of dietary lipid in feces. Energy expenditure and physical activity were not increased in ACSL5IKO mice. Mice deficient in intestinal ACSL5 display significantly reduced energy intake during HFD, but not chow feeding. When HFD intake of control mice was matched to ACSL5IKO during pair-feeding studies, no differences in body weight or fat mass gain were observed between groups. Postprandial GLP-1 and PYY were significantly elevated in ACSL5IKO mice secondary to increased FA content in the distal small intestine. Blockade of GLP-1 signaling by administration of a long-acting GLP-1 receptor antagonist partially restored HFD intake of ACSL5IKO. CONCLUSIONS: These data indicate that intestinal ACSL5 serves as a critical regulator of energy balance, protecting mice from diet-induced obesity exclusively by increasing satiety and reducing food intake during HFD feeding. The reduction in food intake observed in ACSL5IKO mice is driven, in part, by increased postprandial GLP-1 and PYY secretion. These effects are only observed during HFD feeding, suggesting that altered processing of dietary fat following intestinal ACSL5 ablation contributes to GLP-1 and PYY mediated increases in satiety.

Effect of inulin on breath hydrogen, postprandial glycemia, gut hormone release, and appetite perception in RYGB patients: a prospective, randomized, cross-over pilot study.

BACKGROUND AND OBJECTIVE: Large intestinal fermentation of dietary fiber may control meal-related glycemia and appetite via the production of short-chain fatty acids (SCFA) and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We investigated whether this mechanism contributes to the efficacy of the Roux-en-Y gastric bypass (RYGB) by assessing the effect of oligofructose-enriched inulin (inulin) vs. maltodextrin (MDX) on breath hydrogen (a marker of intestinal fermentation), plasma SCFAs, gut hormones, insulin and blood glucose concentrations as well as appetite in RYGB patients. METHOD: Eight RYGB patients were studied on two occasions before and ~8 months after surgery using a cross-over design. Each patient received 300 ml orange juice containing 25 g inulin or an equicaloric load of 15.5 g MDX after an overnight fast followed by a fixed portion snack served 3 h postprandially. Blood samples were collected over 5 h and breath hydrogen measured as well as appetite assessed using visual analog scales. RESULTS: Surgery increased postprandial secretion of GLP-1 and PYY (P ≤ 0.05); lowered blood glucose and plasma insulin increments (P ≤ 0.05) and reduced appetite ratings in response to both inulin and MDX. The effect of inulin on breath hydrogen was accelerated after surgery with an increase that was earlier in onset (2.5 h vs. 3 h, P ≤ 0.05), but less pronounced in magnitude. There was, however, no effect of inulin on plasma SCFAs or plasma GLP-1 and PYY after the snack at 3 h, neither before nor after surgery. Interestingly, inulin appeared to further potentiate the early-phase glucose-lowering and second-meal (3-5 h) appetite-suppressive effect of surgery with the latter showing a strong correlation with early-phase breath hydrogen concentrations. CONCLUSION: RYGB surgery accelerates large intestinal fermentation of inulin, however, without measurable effects on plasma SCFAs or plasma GLP-1 and PYY. The glucose-lowering and appetite-suppressive effects of surgery appear to be potentiated with inulin.

Fasting and post prandial pancreatic and enteroendocrine hormone levels in obese and non-obese participants.

Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.

New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy.

It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.

Changes in ghrelin, GLP-1, and PYY levels after diet and exercise in obese individuals.

OBJECTIVE: Diet and exercise, which are the building blocks of obesity management, provide weight loss by creating a negative energy balance. However, the effect of energy deficit induced by long-term diet and exercise on appetite hormones remains unclear. The study was designed to determine the effect of a 12-week diet and exercise program applied to obese individuals on the levels of appetite hormones, namely, ghrelin, GLP-1, and PYY. METHODS: A total of 62 obese individuals (BMI≥30) and 48 healthy controls (BMI 18.50-29.99) participated in the study. Appropriate diet (1000-1500 kcal/day) and exercise (at least 5000 steps/day) programs were applied to obese individuals according to age, gender, and BMI. The ghrelin, GLP-1, and PYY values of the participants were analyzed by the ELISA method and commercial kit by taking venous blood samples before and after 12 weeks of treatment. RESULTS: While ghrelin levels of individuals decreased significantly after diet and exercise, PYY levels increased significantly. However, despite the treatment applied, the GLP-1 and PYY levels of the case group did not reach the levels of the control group. CONCLUSION: Long-term diet and exercise intervention had a positive effect on appetite regulation hormones. It reduced ghrelin levels after treatment. Associated weight loss was facilitated. In the case group, increased satiety hormones after combined treatment supported the maintenance of body weight by increasing satiety.

Gut peptides before and following Roux-En-Y gastric bypass: A systematic review and meta-analysis.

A systematic search was conducted in Medline Ovid, Embase, Scopus, and Cochrane Central Register of Controlled Trials up until March 2021 following PRISMA guidelines. Studies included evaluated ghrelin, GLP-1, PYY or appetite sensation via visual analogue scales (VASs) before and after Roux-en-Y gastric bypass (RYGB) in adults. A multilevel model with random effects for study and follow-up time points nested in study was fit to the data. The model included kcal consumption as a covariate and time points as moderators. Among the 2559 articles identified, k = 47 were included, among which k = 19 evaluated ghrelin, k = 40 GLP-1, k = 22 PYY, and k = 8 appetite sensation. Our results indicate that fasting ghrelin levels are decreased 2 weeks post-RYGB (p = 0.005) but do not differ from baseline from 6 weeks to 1-year post-RYGB. Postprandial ghrelin and fasting GLP-1 levels were not different from pre-surgical values. Postprandial levels of GLP-1 increased significantly from 1 week (p < 0.001) to 2 years post-RYGB (p < 0.01) compared with pre-RYGB. Fasting PYY increased at 6 months (p = 0.034) and 1 year (p = 0.029) post-surgery; also, postprandial levels increased up to 1 year (p < 0.01). Insufficient data on appetite sensation were available to be meta-analyzed.

Satiety: a gut-brain-relationship.

Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro intestinal (GI) tract, enteroendocrine cells (EECs) emit satiety signals such as cholecystokinin (CCK), glucagon like peptide-1 (GLP-1) and peptide YY (PYY), which can then communicate with the vagus nerve to control food intake. More specifically, satiety has been shown to be particularly affected by the GLP-1 hormone and its receptor agonists that have lately been acknowledged as a promising way to reduce weight. In addition, there is increasing evidence that normal flora is also involved in the peripheral, central, and reward system that impact satiety. Moreover, neurologic pathways control satiety through neurotransmitters. In this review, we discuss the different roles of each of the GLP-1 hormone and its agonist, gut microbiomes, as well as neurotransmitters and their interconnected relation in the regulation of body's satiety homeostasis.

Proteomics of appetite-regulating system influenced by menstrual cycle and intensive exercise in female athletes: a pilot study.

Female athletes who endure intense training are at risk of developing the 'female athlete triad,' making energy intake management crucial. However, the fluctuations in estradiol and progesterone levels throughout the menstrual cycle present a challenge in maintaining consistent energy intake. This study aimed to uncover the underlying factors associated with appetite regulation linked to menstrual phases and exercise using proteomic approach. Five female athletes engaged in 60 min of bicycle exercise, followed by 90 min of rest, during both the follicular and luteal phases. Serum samples were collected before, during, and after exercise, and the serum proteome was analyzed using 2D-gel electrophoresis. A total of 511 spots were detected in the subjects' serum profiles, with significant decreases observed in haptoglobin during the luteal phase and complement component 3 during bicycle training. Unsupervised learning with a generalized estimating equation analysis showed that serum peptide YY (PYY), an appetite suppressor, significantly influenced the fluctuations of serum proteins induced by exercise (p < 0.05). Regression analysis demonstrated a positive correlation between PYY and serum IgM (R = 0.87), implying that the intestinal environment and the immune response in female athletes may contribute to appetite regulation.

Low- and high-load resistance training exercise to volitional fatigue generate exercise-induced appetite suppression.

Research on exercise-induced appetite suppression often does not include resistance training (RT) exercise and only compared matched volumes. PURPOSE: To compare the effects of low-load and high-load RT exercise completed to volitional fatigue on appetite-regulation. METHODS: 11 resistance-trained males (24 ± 2 y) completed 3 sessions in a crossover experimental design: 1) control (CTRL); 2) RT exercise at 30% 1-repetition maximum (RM); and 3) RT exercise at 90% 1-RM. RT sessions consisted of 3 sets of 5 exercises completed to volitional fatigue. Acylated ghrelin, active glucagon-like peptide-1 (GLP-1), active peptide tyrosine (PYY), lactate, and subjective appetite perceptions were measured pre-exercise, 0-, 60-, and 120-min post-exercise. Energy intake was recorded the day before, of, and after each session. RESULTS: Lactate was elevated following both 30% (0-, 60-, 120-min post-exercise) and 90% (0-, 60-min post-exercise; P < 0.001, d > 3.92) versus CTRL, with 30% greater than 90% (0-min post-exercise; P = 0.011, d = 1.14). Acylated ghrelin was suppressed by 30% (P < 0.007, d > 1.22) and 90% (P < 0.028, d > 0.096) post-exercise versus CTRL, and 30% suppressed concentrations versus 90% (60-min post-exercise; P = 0.032, d = 0.95). There was no effect on PYY (P > 0.171, ηp2 <0.149) though GLP-1 was greater at 60-min post-exercise in 90% (P = 0.052, d = 0.86) versus CTRL. Overall appetite was suppressed 0-min post-exercise following 30% and 90% versus CTRL (P < 0.013, d > 1.10) with no other differences (P > 0.279, d < 0.56). There were no differences in energy intake (P > 0.101, ηp2 <0.319). CONCLUSIONS: RT at low- and high-loads to volitional fatigue induced appetite suppression coinciding with changes in acylated ghrelin though limited effects on anorexigenic hormones or free-living energy intake were present.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

Isomaltulose Enhances GLP-1 and PYY Secretion to a Mixed Meal in People With or Without Type 2 Diabetes as Compared to Saccharose.

SCOPE: Secretion of the gut hormones glucagon-like peptide (GLP-1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve ß-cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1 h before a standardized mixed meal test (MMT) on GLP-1, PYY, glucose-dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM). METHODS AND RESULTS: Fifteen healthy volunteers and 15 patients with T2DM consumed either 50 g ISO or SAC 1 h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50 g ISO as compared to SAC induced a significant increase in GLP-1, GIP, and PYY responses over 2 h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP-1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC. CONCLUSION: A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP-1 and enhances GIP release in response to a subsequent complex meal.

Relationship of Glucagon-like Peptide 1 and Peptide YY with Catch-up Growth in Children Born Small for Gestational Age

Objective: Children born small for gestational age (SGA) are at a greater risk of developing insulin resistance, type 2 diabetes, and cardiovascular disease in adulthood. Gastrointestinal peptides, some secreted by intestinal L cells, regulate glucose and lipid metabolism and act on the hypothalamus to regulate energy homeostasis. The aim of this study was to explore whether gastrointestinal peptides are involved in metabolic disorders in SGA, which remains unclear. Methods: The secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were investigated in prepubertal children born SGA, the differences between catch-up growth and persistent short stature were compared, and correlation with glucose and lipid metabolism was analyzed. GLP-1, PYY, insulin-like growth factor 1, glucose, insulin, and lipid concentrations were analyzed in prepubertal children aged 4-10 years, stratified into three groups: short-SGA (SGA-s), catch-up growth SGA, and normal growth appropriate for gestational age (AGA). Results: Fasting GLP-1 and PYY concentrations were significantly lower in the SGA group than in the AGA group (p<0.05), and the GLP-1 level in infants born SGA with catch-up growth was lower than that in the SGA-s group (p<0.05). In the SGA population, GLP-1 showed a weak negative correlation with catch-up growth (r=-0.326) and positive correlation with fasting insulin (r=0.331). Conclusion: Lower GLP-1 concentrations may be associated with abnormal glucose metabolism in prepubertal children born SGA with catch-up growth. This is indirect evidence that impaired intestinal L cell function may be involved in the development of metabolic complications in SGA children.

RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells.

BACKGROUND & AIMS: RET tyrosine kinase is necessary for enteric nervous system development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility. METHODS: RetCFP/+ mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET regulates gut motility in vivo, genetic, and pharmacologic approaches were used to disrupt RET in all RET-expressing cells, a subset of enteric neurons, or intestinal epithelial cells. RESULTS: Distinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the epithelium, rather than in enteric neurons, slowed GI motility selectively in male mice. RET kinase inhibition phenocopied this effect. Most RET+ epithelial cells were either enterochromaffin cells that release serotonin or L-cells that release peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), both of which can alter motility. RET kinase inhibition exaggerated PYY and GLP-1 release in a nutrient-dependent manner without altering serotonin secretion in mice and human organoids. PYY receptor blockade rescued dysmotility in mice lacking epithelial RET. CONCLUSIONS: RET signaling normally limits nutrient-dependent peptide release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.

Neurohormonal response patterns to hunger, satiation, and postprandial fullness in normal weight, anorexia nervosa, and obesity.

BACKGROUND: Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN. MATERIAL & METHODS: During an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs). RESULTS: A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK. CONCLUSION: Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.