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Molecular Metabolism Jan 2022Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious...
Peptide-YY/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries.
OBJECTIVE
Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce.
METHODS
In this study, we utilized long-acting analogues of GLP-1 and PYY (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions.
RESULTS
Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY + Fc-GLP-1R agonist administration.
CONCLUSIONS
These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. These data also highlight the potential association between the gut-brain axis in control of metabolic homeostasis.
Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Eating; Energy Intake; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypothalamus; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide YY; Weight Loss
PubMed: 34781035
DOI: 10.1016/j.molmet.2021.101392 -
Scientific Reports Jan 2017Altered levels of colonic peptide YY (PYY) have been reported in patients suffering from functional and inflammatory bowel disorders. While the involvement of...
Altered levels of colonic peptide YY (PYY) have been reported in patients suffering from functional and inflammatory bowel disorders. While the involvement of neuropeptide Y (NPY) and Y receptors in the regulation of nociception is well established, the physiological role of PYY in somatic and visceral pain is poorly understood. In this work, the role of PYY in pain sensitivity was evaluated using PYY knockout (PYY) mice and Y2 receptor ligands. PYY mice were more sensitive to somatic thermal pain compared to wild type (WT) mice. Visceral pain was assessed by evaluating pain-related behaviors, mouse grimace scale (MGS) and referred hyperalgesia after intrarectal administration of allyl isothiocyanate (AITC, 1 or 2%) or its vehicle, peanut oil. The pain-related behaviors induced by AITC were significantly exaggerated by PYY deletion, whereas the MGS readout and the referred hyperalgesia were not significantly affected. The Y2 receptor antagonist, BII0246, increased pain-related behaviors in response to intrarectal AITC compared to vehicle treatment while the Y2 receptor agonist, PYY(3-36), did not have a significant effect. These results indicate that endogenous PYY has a hypoalgesic effect on somatic thermal and visceral chemical pain. The effect on visceral pain seems to be mediated by peripheral Y2 receptors.
Topics: Animals; Behavior, Animal; Hot Temperature; Hyperalgesia; Isothiocyanates; Mice; Mice, Knockout; Peptide YY; Receptors, Gastrointestinal Hormone
PubMed: 28106168
DOI: 10.1038/srep40968 -
Bioscience, Biotechnology, and... Nov 2018The study was aimed to compare the satiating effect of various protein hydrolysates in rats and examine the underlying mechanism associated with the satiety hormones....
The study was aimed to compare the satiating effect of various protein hydrolysates in rats and examine the underlying mechanism associated with the satiety hormones. Food intake and portal satiety hormone levels were measured in rats. Enteroendocrine cell-lines were employed to study the direct effect of protein hydrolysates on gut hormone secretions. The results showed that oral preload of wheat gluten hydrolysate (WGH) suppressed food intake greater and longer than other hydrolysates. The portal peptide-YY levels in WGH-treated rats at 2 h and 3 h were higher than those in control- and lactalbumin hydrolysate (LAH)-treated rats. In a distal enteroendocrine cell model, WGH more potently stimulated glucagon-like peptide-1 secretion than LAH, and the effect was largely enhanced by pepsin/pancreatin digestion of WGH. These results suggest WGH is potent in activating enteroendocrine cells to release satiety hormones leading to the prolonged suppression of food intake.
Topics: Animals; Cell Line; Enteroendocrine Cells; Feeding Behavior; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glutens; Hydrolysis; Male; Mice; Pancreatin; Pepsin A; Peptide YY; Rats, Wistar; Satiation; Triticum
PubMed: 30096043
DOI: 10.1080/09168451.2018.1505482 -
Scientific Reports Jun 2023Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like...
Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.
Topics: Humans; Animals; Rats; Glucagon-Like Peptide 1; Glycemic Control; Neuropeptides; Weight Loss; Peptide YY
PubMed: 37308546
DOI: 10.1038/s41598-023-36178-1 -
Cancer Prevention Research... Feb 2023Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We...
UNLABELLED
Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We investigated whether circulating levels of the gut hormones ghrelin (analyzed as acyl ghrelin) and Peptide YY (PYY) were associated with subsequent colorectal cancer risk, including clinical and molecular tumor subtypes. We also provide descriptive data on these hormones in relation to background participant characteristics and metabolic biomarkers. This population-based study included 1,010 matched case-control pairs with a median of 12.3 years of follow-up. Acyl ghrelin and PYY were measured by multiplex immunoassay. Data on KRAS and BRAF mutations and microsatellite instability (MSI) status were available for 704 and 708 cases, respectively. Conditional logistic regression models estimated association to colorectal cancer risk. Partial correlation and linear regression were used to investigate relationships between background and metabolic variables and variation in plasma gut hormone concentrations. Acyl ghrelin was not clearly associated with colorectal cancer risk (multivariable OR per 1 SD increase: 1.11; 95% CI, 1.00-1.23). Positive associations were observed for specific subtypes, in particular BRAF-mutated colorectal cancer and right-sided colon cancer, although with nonsignificant heterogeneity. PYY was not related to colorectal cancer risk (multivariable OR per 1 SD: 1.04; 95% CI, 0.95-1.14) or any tumor subtype. In the control participants, ghrelin was inversely correlated with BMI, and PYY was positively correlated with C-peptide and insulin levels. These findings provide limited support for a possible role for ghrelin in colorectal cancer development, primarily in specific anatomical and molecular tumor subtypes.
PREVENTION RELEVANCE
The findings of this study do not support a major role for the metabolic gut hormones ghrelin and PYY in colorectal cancer development but suggest the possibility of an involvement for ghrelin in specific tumor subtypes. Elucidating subtype-specific risk factors and mechanisms of carcinogenesis may have implications for precision prevention.
Topics: Humans; Peptide YY; Gastrointestinal Hormones; Obesity; Colorectal Neoplasms
PubMed: 36367526
DOI: 10.1158/1940-6207.CAPR-22-0325 -
International Journal of Molecular... May 2020Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of...
Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of the systemic effects of these hormones, very little is known concerning the mechanisms by which nutrients, such as dietary fats, can promote the expression of genes involved in L-cell hormone production. We have tested the role of various dietary fats and found that after hydrolysis into free fatty acids (FFA's), there is a differential response in the extent to which they induce PYY gene and protein production. The effect of FFA's also seems to relate to triglyceride (TG) re-esterification rate, with MUFA re-esterifying faster with lower PYY production. We have also found that there are differences in potency of FFA's based on their desaturation patterns in vitro. The potency effect of FFA's is influenced by the rate of TG re-esterification, such that the longer FFA's are in contact with L-cells, the more PYY they produce. We found that chronic consumption of high-fat diets enables the small intestine to re-esterify FFA's into TG faster and earlier which resulted in a blunted postprandial PYY response. Lastly, we found that FFA's induce X-box-binding protein-1 activation (Xbp1s) in L-cells and that adenoviral delivery of Xbp1s was sufficient to induce PYY gene expression. Taken together, the present work indicates that dietary fat can induce satiety, in part, prior to re-esterification. Chronic high-fat diet consumption increases the rate of re-esterification which diminishes satiety and may lead to increased food intake. Targeting intestinal TG synthesis may prove beneficial in restoring obesity-associated reductions in postprandial satiety.
Topics: Animals; Cell Line, Tumor; Diet, High-Fat; Eating; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; L Cells; Lipid Metabolism; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide YY; Postprandial Period; RNA Splicing; Satiety Response; Triglycerides; X-Box Binding Protein 1
PubMed: 32397573
DOI: 10.3390/ijms21093368 -
The American Journal of Clinical... Feb 2010Epidemiologic studies suggest that childbearing is an important contributor to the development of obesity in many women and that breastfeeding may be protective. Ghrelin...
BACKGROUND
Epidemiologic studies suggest that childbearing is an important contributor to the development of obesity in many women and that breastfeeding may be protective. Ghrelin and peptide YY (PYY) are gut hormones involved in appetite regulation and energy homeostasis and are biological neuroendocrine signals that potentially affect body weight and adiposity.
OBJECTIVE
This study evaluated whether fasting or postprandial ghrelin or PYY is different between lactating and nonlactating postpartum women matched for age, body weight, and adiposity.
DESIGN
Ten postpartum lactating women (mean + or - SD: 28.1 + or - 4.9 y of age, 69.2 + or - 11.3 kg, 35.4 + or - 6.6% body fat) and 8 nonlactating women (28.8 + or - 7.6 y of age, 75.6 + or - 13.7 kg, 37.5 + or - 6.5% body fat) at 4-5 wk postpartum underwent measurements of body weight, body composition, and ghrelin and PYY responses to a standardized meal (350 kcal). Seven never-pregnant women served as control subjects (29.7 + or - 4.1 y of age, 60.4 + or - 4.8 kg, 25.5 + or - 2.0% body fat).
RESULTS
Ghrelin concentrations decreased, whereas PYY concentrations increased significantly (P < 0.05) in response to the meal, but fasting or meal-induced changes were not significantly different between lactating and nonlactating women. The fasting ghrelin concentration correlated with body mass index (r = -0.53, P < 0.05) and was significantly lower in postpartum than in control women (894.9 + or - 247.7 compared with 1316.9 + or - 241.0 pg/mL), even after adjustment for body mass index.
CONCLUSIONS
Our data do not support the notion that ghrelin, PYY, or both are plausible neuroendocrine signals that influence body weight regulation during lactation. They suggest, however, that ghrelin may change with increased adiposity in the postpartum state and may potentially play a role in body weight regulation after child birth.
Topics: Adult; Basal Metabolism; Body Composition; Body Mass Index; Body Weight; Calorimetry, Indirect; Female; Ghrelin; Humans; Lactation; Longitudinal Studies; Peptide YY; Postpartum Period
PubMed: 20007306
DOI: 10.3945/ajcn.2009.28616 -
British Journal of Pharmacology Nov 2013Immune challenge of mice with Bacille Calmette-Guérin (BCG) has been reported to cause transient weight loss and a behavioural sickness response. Although BCG-induced...
BACKGROUND AND PURPOSE
Immune challenge of mice with Bacille Calmette-Guérin (BCG) has been reported to cause transient weight loss and a behavioural sickness response. Although BCG-induced depression involves the kynurenine pathway, weight loss occurs independently of this factor. Because neuropeptide Y (NPY) and peptide YY (PYY) are involved in the regulation of food intake, we hypothesized that they play a role in the BCG-induced weight loss.
EXPERIMENTAL APPROACH
Male wild-type, PYY knockout (PYY-/-), NPY knockout (NPY-/-) and NPY-/-;PYY-/- double knockout mice were injected with vehicle or BCG (approximately 10(8) colony-forming units per mouse), and their weight, locomotion, exploration and ingestion were recorded for 2 weeks post-treatment.
KEY RESULTS
Deletion of PYY and NPY aggravated the BCG-induced loss of body weight, which was most pronounced in NPY-/-;PYY-/- mice (maximum loss: 15%). The weight loss in NPY-/-;PYY-/- mice did not normalize during the 2 week observation period. BCG suppressed the circadian pattern of locomotion, exploration and food intake. However, these changes took a different time course than the prolonged weight loss caused by BCG in NPY-/-;PYY-/- mice. The effect of BCG to increase circulating IL-6 (measured 16 days post-treatment) remained unaltered by knockout of PYY, NPY or NPY plus PYY.
CONCLUSIONS AND IMPLICATIONS
These data show that NPY and PYY are both required to protect from the action of BCG-evoked immune challenge to cause prolonged weight loss and disturb energy balance. The findings attest to an important role of NPY and PYY in orchestrating homeostatic reactions to infection and immune stimulation.
Topics: Animals; BCG Vaccine; Behavior, Animal; Circadian Rhythm; Corticosterone; Eating; Energy Metabolism; Exploratory Behavior; Female; Interleukin-6; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropeptide Y; Peptide YY; Time Factors; Weight Loss
PubMed: 23992467
DOI: 10.1111/bph.12354 -
Nutrients Feb 2021Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents...
Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential confounders on their concentrations were also analysed. Eighty-nine adolescents were included in this study (AN = 30, OB = 30, and CG = 29). Anthropometric measurements and psychometric assessment of depressive symptoms, eating behaviours, body attitudes, and fasting serum levels of NPY and PYY were analysed. The AN group presented severe depressive symptoms, while the OB group held different attitudes towards the body. The levels of NPY were lower in the AN and OB groups as compared with the CG. The PYY levels were higher in the OB group than in the AN group and the CG. The severity of eating disorder symptoms predicted fasting serum concentrations of NPY. Lower levels of NPY in AN, as well as in OB suggests the need to look for a common link in the mechanism of this effect. Higher level of PYY in OB may be important in explaining complex etiopathogenesis of the disease. The psychopathological symptoms may have an influence on the neurohormones regulating metabolism.
Topics: Adolescent; Anorexia Nervosa; Blood Glucose; Body Mass Index; Child; Depression; Fasting; Feeding Behavior; Female; Humans; Insulin; Male; Neuropeptide Y; Obesity; Peptide YY
PubMed: 33670342
DOI: 10.3390/nu13020598 -
Journal of Clinical Research in... Mar 2024Children born small for gestational age (SGA) are at a greater risk of developing insulin resistance, type 2 diabetes, and cardiovascular disease in adulthood....
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.
Topics: Child; Infant, Newborn; Humans; Peptide YY; Gestational Age; Diabetes Mellitus, Type 2; Infant, Small for Gestational Age; Insulin Resistance; Insulin; Glucose; Glucagon-Like Peptide 1
PubMed: 37847108
DOI: 10.4274/jcrpe.galenos.2023.2023-5-21