peptide-yy and Hypertension

The present opinion article provides an overview of the key improvements in metabolic and cardiovascular health following Roux-en-Y Gastric Bypass (RYGB). Some clinically important long-term complications of RYGB are also briefly described to contextualise the potential value of finding selective non-surgical means of replicating only the beneficial aspects of RYGB. Three biological responses linked to changes in gastrointestinal tract structure and function post-RYGB, that are implicated in the clinical efficacy of RYGB and that have actual or potential applications as non-surgical mimetic based approaches are addressed. These are (1) exaggerated post-prandial gut hormone responses; (2) local increases in undiluted bile in the gut lumen and augmented circulating bile acid and FGF19 concentrations and (3) compositional changes in the gut microbiota.

Topics: Adaptation, Physiological; Bile Acids and Salts; Fibroblast Growth Factors; Gastric Bypass; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Hypertension; Peptide Fragments; Peptide YY; Postprandial Period

Obesity is a disease that develops as a result of long-term positive energy balance. In recent years, the influence of gut microflora composition, as a potential factor affecting the energy balance and contributing to fat accumulation, has been studied. It seems that bacteria can affect host energy balance through several mechanisms, such as increased fermentation of undigested polysaccharides and obtaining extra energy from the portion of food, reduced expression of FIAF (fasting-induced adipocyte factor) in the enterocytes with inhibitory activity towards intestinal lipoprotein lipase, and the increased release of peptide YY that slows the intestinal motility. It is also believed that changes in the composition of gut microflora may be one of the factors that induce systemic microinflammation in the obese, an important link in the pathogenesis of obesity related complications, including dyslipidaemia, hypertension and type 2 diabetes. However, the results of previous studies are inconclusive. Many of them have been carried out in an animal model and were not confirmed in studies involving humans. These discrepancies may be due to different composition of the diet, distinct physiological gut microflora and the methodology used in these studies. The present article reviews the current literature on the potential role of gut microflora in the pathogenesis of obesity.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Dyslipidemias; Energy Metabolism; Enterocytes; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Hypertension; Intestines; Lipase; Microbiota; Obesity; Peptide YY

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Topics: Adiponectin; Aldosterone; Animals; Appetite; Endothelium, Vascular; Energy Metabolism; Ghrelin; Humans; Hyperinsulinism; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney; Leptin; Mice; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Obesity; Peptide Hormones; Peptide YY; Receptors, Cell Surface; Receptors, Leptin; Renin-Angiotensin System; Repressor Proteins; Satiation; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Sympathetic Nervous System; Transcription Factors

Neuropeptide Y is a 36 amino acid peptide that was originally discovered in extracts of porcine brain. The peptide has a broad distribution in the central or peripheral nervous system. Receptors for this peptide were originally subdivided into postsynaptic Y-1 receptors and presynaptic Y-2 receptors. The Y-1 receptor has recently been cloned and appears to mediate several effects of NPY including vasoconstriction and an anxiolytic effect in animal models of anxiety. The Y-2 receptor inhibits the release of neurotransmitters in the CNS by the inhibition of the mobilization of intracellular calcium. Additional receptors have been proposed including a Y-3 receptor that recognizes NPY but not the related endocrine peptide, PYY. The functional importance of these newer receptors remains to be established. The absence of useful antagonists has made the study of NPY a challenge for investigators in the field. The potential utility of such molecules is discussed.

Topics: Animals; Brain; Cardiovascular Physiological Phenomena; Cognition; Feeding Behavior; Humans; Hypertension; Neuropeptide Y; Neurotransmitter Agents; Peptide YY; Peptides; Receptors, Neuropeptide Y; Receptors, sigma

By reducing their metabolism, dipeptidyl peptidase 4 inhibition (DPP4I) enhances the effects of numerous peptides including neuropeptide Y

Topics: 2-Methoxyestradiol; Animals; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Collagen; Dipeptidyl-Peptidase IV Inhibitors; Female; Hypertension; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors.

Topics: Angiotensin II; Animals; Cell Proliferation; Collagen; Dipeptidyl-Peptidase IV Inhibitors; Estrenes; Fibroblasts; GTP-Binding Proteins; Hypertension; Indoles; Maleimides; Myocardium; Neuropeptide Y; Peptide Fragments; Peptide YY; Pertussis Toxin; Protein Kinase C; Pyrrolidinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors for Activated C Kinase; Signal Transduction; Sitagliptin Phosphate; Type C Phospholipases

Hypertension is a major health problem and is usually associated with common conditions such as obesity, which contribute to clinical cardiac dysfunction. The role of energy homeostasis hormones such as ghrelin and PYY 3-36 in cardiovascular function remains incompletely understood. Therefore, the aim of our study was to explore the potential differences in concentrations of ghrelin forms and PYY 3-36 circulating in obese patients with grade 1 and grade 2 hypertension, with higher and lower BMI and without and with insulin resistance as well as to determine whether these hormones may be associated with left ventricular hypertrophy.. A total of 142 adult subjects were studied in three subgroups: lean (BMI < 25 kg/m(2)) normotensive subjects and obese subjects (BMI 30.0-34.9 kg/m(2)), and obese subjects (BMI 35.0-39.9 kg/m(2)) under hypertensive treatment for at least 9 years. Fasting blood glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), lipid profile, urinic acid, acylated ghrelin (A-Ghr), total ghrelin (T-Ghr), and PYY 3-36 were measured. Insulin resistance was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). We also echocardiographically assessed left ventricular mass (LVM) index (LVMI = LVM/height(2.7)). We evaluated the association between plasma T-Ghr, A-Ghr, PYY 3-36 levels with LVMI and other measured factors using univariate and multivariate analysis.. There were significant differences between BMI, waist circumference (WC), LVMI, hs-CRP and A-Ghr/nonacylated ghrelin (NA-Ghr) ratio (in the two obese subgroups. There was no significant difference between T-Ghr, A-Ghr and PYY 3-36 levels between obese subgroups. T-Ghr and PYY 3-36 were significantly lower in obese patients than in the control group, whereas A-Ghr levels did not differ between obese and controls. A-Ghr/NA-Ghr ratio was significantly higher in patients with second-degree hypertension and BMI 35.0-39.9 kg/m(2) than in patients with first-degree hypertension and BMI 30.0-34.9 kg/m(2). There were negative associations between T-Ghr, NA-Ghr or PYY 3-36 and LVMI (r = -0.49, p = 0.0001; r = -0.47, p = 0.0001; or r = -0.18, p = 0.029, respectively) and positive association between A-Ghr/NA-Ghr ratio and LVMI (r = 0.3, p = 0.0003). T-Ghr and NA-Ghr, were associated negatively with fasting insulin (r = -0.31, p = 0.0025; and r = -0.36, p = 0.001, repectively), while A-Ghr/NA-Ghr ratio was positively associated with BMI and fasting insulin (r = 0.23, p = 0.041; r = 0.3, p = 0.0045, respectively). T-Ghr, A-Ghr, and NAGhr were also inversely related to HOMA-IR indices in obese patients (r = -0.43, p = 0.001; r = -0.32, p = 0.0359; r = -0.35, p = 0.001, respectively). In insulin-resistant obese subjects T-Ghr and NA-Ghr correlated negatively with HOMA-IR (r = -0.34, p = 0.0015; r = -0.28, p = 0.0116, respectively). LVMI was associated negatively with T-Ghr, NA-Ghr and PYY 3-36 (r = -0.49, p = 0.0001; r = -0.47, p = 0.0001; r = -0.18, p = 0.029, respectively). In addition, LVMI was positively associated with A-Ghr/NA-Ghr ratio (r = 0.30, p = 0.0003).. Plasma ghrelin forms and PYY 3-36 levels are associated with LVMI. These associations indicate a possible interaction between gut peptides and the cardiovascular system in hypertension and obesity.

Topics: Acylation; Adult; Body Mass Index; C-Reactive Protein; Female; Ghrelin; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin; Insulin Resistance; Male; Middle Aged; Multivariate Analysis; Obesity; Peptide YY; Reference Values; Waist Circumference

Dipeptidyl peptidase IV inhibitors are a new class of antidiabetic drugs. It is urgent, therefore, to fully understand the pharmacology of these inhibitors. Although dipeptidyl peptidase IV metabolizes at least 24 endogenous substrates, the pharmacological consequences of inhibiting the metabolism of most of these substrates is unknown. Our previous results show that Y(1) receptors, but not Y(2) receptors, enhance renovascular responses to angiotensin II in kidneys from genetically susceptible animals (spontaneously hypertensive rats). Dipeptidyl peptidase IV converts peptide YY(1-36) (circulating hormone) to peptide YY(3-36), and peptide YY(1-36) is a Y(1)-receptor agonist, whereas peptide YY(3-36) is a selective Y(2)-receptor agonist. Therefore, it is conceivable that inhibition of dipeptidyl peptidase IV in genetically susceptible kidneys may increase the ability of peptide YY(1-36) to potentiate angiotensin II-induced renal vasoconstriction. Here we demonstrate that in kidneys from spontaneously hypertensive rats 1) peptide YY(1-36) potentiates renovascular responses to angiotensin II, whereas peptide YY(3-36) has little effect, 2) 3-N-[(2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine (P32/98) (dipeptidyl peptidase IV inhibitor) augments the ability of peptide YY(1-36) to enhance renovascular responses to angiotensin II, 3) dipeptidyl peptidase IV is expressed in preglomerular microvessels and glomeruli, 4) kidneys metabolize arterial PYY(1-36) to PYY(3-36) via a mechanism blocked by P32/98, and 5) preglomerular microvessels and glomeruli convert peptide YY(1-36) to peptide YY(3-36), and this conversion is inhibited by P32/98. We conclude that dipeptidyl peptidase IV is expressed in the renal microcirculation and inhibition of this ecto-enzyme causes arterial PYY(1-36) to more effectively enhance angiotensin II-induced renal vasoconstriction in genetically susceptible kidneys.

Topics: Angiotensin II; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Hypertension; Kidney; Male; Peptide YY; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction

The Gi pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-coupled pancreatic polypeptide (PP)-fold peptide receptors Y1 and Y2 are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y1-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II-induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y2-receptor agonist (peptide YY(3-36); 6 nM) only slightly potentiated angiotensin II-induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y1-receptor nor the Y2-receptor agonist increased basal perfusion pressure. BIBP3226 (1 micromol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 micromol/L, highly selective Y2-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY(3-36), respectively. Y1-receptor and Y2-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y1-receptor-induced and Y2-receptor-induced potentiation of angiotensin II-mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 microg/kg IV, blocks Gi proteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y1-receptor activation markedly enhances angiotensin II-mediated renal vasoconstriction by a mechanism involving Gi. Although Y2 receptors can also potentiate angiotensin II-mediated renal vasoconstriction via Gi, the effect is modest compared with Y1 receptors. These findings may have important implications for the etiology of genetic hypertension.

Topics: Angiotensin II; Animals; Blood Vessels; Blotting, Western; Hypertension; In Vitro Techniques; Kidney; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Perfusion; Pressure; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoconstriction