natriuretic-peptide--c-type and Obesity

The natriuretic peptide (NP) family includes atrial natriuretic peptide (ANP), B-type natriuretic peptide, C-type natriuretic peptide and their receptors NPR-A, NPR-B and NPR-C. The effects exerted by this hormonal system in the control of cardiovascular, renal and endocrine functions have been extensively investigated. Moreover, the involvement of NP in the pathogenesis of cardiovascular diseases has been demonstrated. Among the NP components, NPR-C has been described, at the time of its discovery, as the clearance receptor of NP devoid of any physiological functions. Emerging roles of NPR-C, however, have been highlighted over the last few years in relation to its effects on the cardiovascular system and other organs. These effects appear to be directly mediated through distinct cAMP-dependent intracellular mechanisms. Moreover, evidence has been accumulated on a potential pathophysiological role of NPR-C in human diseases. Ongoing studies from our group are revealing its involvement in the mediation of antiproliferative effects exerted on vascular cells by a molecular variant of human ANP. Thus, a new appraisal of NPR-C is overcoming the traditional view of a mere clearance receptor. This review focuses on the most important evidence supporting an involvement of NPR-C in mediating some of the actions of NP and its direct implication in cardiovascular diseases. The current state of knowledge highlights the need of further studies to better clarify the specific roles of NPR-C in pathophysiological processes.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Peptide, C-Type; Obesity; Phenotype

Natriuretic peptides (NPs) are released from the heart in response to pressure and volume overload. B-type natriuretic peptide (BNP) and N-terminal-proBNP have become important diagnostic tools for assessing patients who present acutely with dyspnea. The NP level reflects a compilation of systolic and diastolic function as well as right ventricular and valvular function. Studies suggest that using NPs in the emergency department can reduce the consumption of hospital resources and can lower costs by either eliminating the need for other, more expensive tests or by establishing an alternative diagnosis that does not require hospital stay. Caveats such as body mass index and renal function must be taken into account when analyzing NP levels. Natriuretic peptide levels have important prognostic value in multiple clinical settings, including in patients with stable coronary artery disease and with acute coronary syndromes. In patients with decompensated heart failure due to volume overload, a treatment-induced drop in wedge pressure is often accompanied by a rapid drop in NP levels. Knowing a patient's NP levels might thus assist with hemodynamic assessment and subsequent treatment titration. Monitoring NP levels in the outpatient setting might also improve patient care and outcomes.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Death, Sudden, Cardiac; Heart Diseases; Heart Failure; Hemodynamics; Humans; Kidney Failure, Chronic; Monitoring, Physiologic; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Obesity; Peptide Fragments; Prognosis; Pulmonary Edema; Pulmonary Embolism; Pulmonary Wedge Pressure; Renal Dialysis; Stroke; Weight Loss

The fact that the heart is able to secrete hormones, which are released in significant amounts in advance of certain cardiac conditions, has resulted in a wide range of opportunities and raised a multitude of questions. These hormones, named natriuretic peptides, possess diuretic, natriuretic and vasodilatory properties. The ones used in daily clinical practice are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and their N-terminal fragments NT-proANP and NT-proBNP, respectively. Although most studies currently involve the use of BNP, the number involving NT-proBNP is expected to increase substantially in coming years because its level is less variable and its half-life longer. Nevertheless, at present there appears to be sufficient evidence to suggest that the plasma levels of these hormones will be extremely useful for the diagnosis, prognosis, screening, pharmacological monitoring, and treatment of patients with heart failure.

Topics: Atrial Natriuretic Factor; Biomarkers; Death, Sudden, Cardiac; Heart Failure; Hospitalization; Humans; Lung Diseases; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Obesity; Prognosis; Renal Insufficiency; Ventricular Dysfunction, Left

Topics: Animals; Atrial Natriuretic Factor; Catecholamines; Fatty Acids, Nonesterified; Humans; Lipolysis; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Obesity

C-type natriuretic peptide (CNP) is an endogenous adipogenesis regulator whose plasma levels in childhood are known, while no data are available on its expression. Our aim was to evaluate both CNP plasma levels and CNP system expression in whole blood obtained from normal-weight (N, n = 24) and obese (O, n = 16) adolescents (age:13.5 ± 0.4 years). Endothelial function was assessed measuring reactive hyperemia index (RHI). CNP plasma levels, evaluated with specific RIA, resulted significantly lower in O than in N (6.1 ± 0.8 vs.15.2 ± 1.3 pg/mL; p < 0.0001), while CNP/NPR-B/NPR-C mRNA, measured by Real-Time PCR, resulted similar in N (4.1 ± 1.7; 5.0 ± 1.6; 2.2 ± 0.9) and in O (4.3 ± 1.6; 3.5 ± 1.1; 2.3 ± 0.8). RHI was significantly lower in O than in N (1.4 ± 0.08 vs.2.1 ± 0.04, p < 0.0001). Dividing all subjects according to the RHI median value, irrespective of the presence or absence of obesity (Group 1 > 1.9, n = 23, Group 2 < 1.9, n = 17), CNP plasma concentrations resulted significantly (p = 0.014) higher in Group 1 (14.6 ± 1.6) than in Group 2 (7.5 ± 1.0), showing a significant correlation with RHI (p = 0.0026), while CNP mRNA expression was, surprisingly, higher in Group 2 (7.0 ± 2.3) than in Group 1 (1.8 ± 0.4; p = 0.02). NPR-B mRNA resulted similar in both Groups (4.3 ± 1.6; 4.7 ± 1.3) and NPR-C significantly higher in Group 2 (p = 0.02). Our data suggest different trends between CNP plasma levels and expression, assessed for the first time in whole blood, that could reflect changes occurring both at CNP transcriptional level in activated leukocytes due to inflammation, and at circulating levels, due to CNP paracrine/autocrine activities. This could represent an interesting area for new therapies able to modulate endothelial dysfunction.

Topics: Adolescent; Body Mass Index; Case-Control Studies; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Natriuretic Peptide, C-Type; Obesity; Receptors, Atrial Natriuretic Factor; RNA, Messenger

C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high-fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP-VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid β-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity.

Topics: Adipocytes; Adipose Tissue; Animals; Diet, High-Fat; Energy Metabolism; Hypertrophy; Insulin Resistance; Lipid Metabolism; Lipolysis; Male; Mice; Mice, Inbred C57BL; Natriuretic Agents; Natriuretic Peptide, C-Type; Obesity

The endogenous peptide C-type natriuretic peptide (CNP) binds its receptor, guanylyl cyclase B (GCB), and is expressed by endothelial cells in diverse tissues. Because the endothelial cells of visceral adipose tissue have recently been reported to play a role in lipid metabolism and inflammation, we investigated the effects of CNP on features of obesity by using transgenic (Tg) mice in which CNP was placed under the control of the Tie2 promoter and was thus overexpressed in endothelial cells (E-CNP). Here we show that increased brown adipose tissue thermogenesis in E-CNP Tg mice increased energy expenditure, decreased mesenteric white adipose tissue (MesWAT) fat weight and adipocyte hypertrophy, and prevented the development of fatty liver. Furthermore, CNP overexpression improved glucose tolerance, decreased insulin resistance, and inhibited macrophage infiltration in MesWAT, thus suppressing pro-inflammation during high-fat diet-induced obesity. Our findings indicate an important role for the CNP produced by the endothelial cells in the regulation of MesWAT hypertrophy, insulin resistance, and inflammation during high-fat diet-induced obesity.

Topics: Adipocytes; Animals; Diet, High-Fat; Endothelial Cells; Energy Metabolism; Gene Expression; Glucose Intolerance; Guanylate Cyclase; Inflammation; Insulin Resistance; Liver; Mice; Mice, Transgenic; Natriuretic Peptide, C-Type; Obesity; RNA, Messenger; Thermogenesis

Obesity is defined as an abnormal increase in white adipose tissue (WAT) and is a major risk factor for type 2 diabetes and cardiovascular disease. Brown adipose tissue (BAT) dissipates energy and correlates with leanness. Natriuretic peptides have been shown to be beneficial for brown adipocyte differentiation and browning of WAT.. Here, we investigated the effects of an optimized designer natriuretic peptide (CD-NP) on murine adipose tissues. In murine brown and white adipocytes, CD-NP activated cGMP production, promoted adipogenesis, and increased thermogenic markers. Consequently, mice treated for 10 days with CD-NP exhibited increased "browning" of WAT. To study CD-NP effects on diet-induced obesity (DIO), we delivered CD-NP for 12 weeks. Although CD-NP reduced inflammation in WAT, CD-NP treated DIO mice exhibited a significant increase in body mass, worsened glucose tolerance, and hepatic steatosis. Long-term CD-NP treatment resulted in an increased expression of the NP scavenging receptor (NPR-C) and decreased lipolytic activity.. NP effects differed depending on the duration of treatment raising questions about the rational of natriuretic peptide treatment in obese patients.

Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Diet; Elapid Venoms; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, C-Type; Obesity; Thermogenesis

C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B (NPR-B), are abundantly distributed in the hypothalamus. To explore the role of central CNP/NPR-B signaling in energy regulation, we generated mice with brain-specific NPR-B deletion (BND mice) by crossing Nestin-Cre transgenic mice and mice with a loxP-flanked NPR-B locus. Brain-specific NPR-B deletion prevented body weight gain induced by a high-fat diet (HFD), and the mesenteric fat and liver weights were significantly decreased in BND mice fed an HFD. The decreased liver weight in BND mice was attributed to decreased lipid accumulation in the liver, which was confirmed by histologic findings and lipid content. Gene expression analysis revealed a significant decrease in the mRNA expression levels of CD36, Fsp27, and Mogat1 in the liver of BND mice, and uncoupling protein 2 mRNA expression was significantly lower in the mesenteric fat of BND mice fed an HFD than in that of control mice. This difference was not observed in the epididymal or subcutaneous fat. Although previous studies reported that CNP/NPR-B signaling inhibits SNS activity in rodents, SNS is unlikely to be the underlying mechanism of the metabolic phenotype observed in BND mice. Taken together, CNP/NPR-B signaling in the brain could be a central factor that regulates visceral lipid accumulation and hepatic steatosis under HFD conditions. Further analyses of the precise mechanisms will enhance our understanding of the contribution of the CNP/NPR-B system to energy regulation.

Topics: Acyltransferases; Animals; Brain; CD36 Antigens; Diet, High-Fat; Energy Metabolism; Fatty Liver; Gene Deletion; Gene Expression Profiling; Hypothalamus; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Natriuretic Peptide, C-Type; Obesity; Organ Size; Proteins; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Signal Transduction; Weight Gain

CNP is a natural regulator of adipogenesis playing a role in the development of obesity in childhood. Aim of the study was to evaluate CNP plasma levels in normal-weight (N), overweight (OW) and obese adolescents (O). Eighty two subjects (age:12.8±2.4, years) without cardiac dysfunction were enrolled and CNP plasma levels were measured by RIA. NT-proBNP, MR-proANP, AGEs, reactive hyperemia index (RHI) and standard clinical chemistry parameters were also measured. O and OW adolescents had higher values of BMI and fat mass than N. CNP levels were significantly lower in OW:4.79[3.29-21.15] and O:3.81[1.55-13.4] than in N:13.21[7.6-37.8]; p<0.0001N vs O, p=0.0003N vs OW). LogCNP values correlated significantly and inversely with BMI z-score, FM%, TF% and circulating levels of CRP, insulin, total cholesterol, LDL, and triglycerides, in addition to an inverse relationship with skin AGEs and a direct correlation with RHI. LogCNP was also inversely associated with LogNT-proBNP and LogMR-proANP values. Using ROC analysis the risk of obesity resulted significantly (p≪0.0001) associated with CNP values (AUC=0.9724). These results suggest that CNP may play a more important role than BNP and ANP related peptides, as risk marker of obesity, in addition to its involvement in adipogenesis and endothelial dysfunction.

Topics: Adolescent; Biomarkers; Body Mass Index; Child; Cohort Studies; Humans; Natriuretic Peptide, C-Type; Natriuretic Peptides; Obesity; Overweight; Radioimmunoassay; Risk Factors; ROC Curve; White People

The high prevalence of obesity in children may increase the magnitude of lifetime risk of cardiovascular disease (CD). At present, explicit data for recommending biomarkers as routine pre-clinical markers of CD in children are lacking. C-type natriuretic peptide (CNP) is assuming increasing importance in CD; in adults with heart failure, its plasma levels are related to clinical and functional disease severity. We have previously reported five different reference intervals for blood CNP as a function of age in healthy children; however, data on plasma CNP levels in obese children are still lacking. Aim of this study was to assess CNP levels in obese adolescents and verify whether they differ from healthy subjects. Plasma CNP was measured in 29 obese adolescents (age: 11.8 ± 0.4 years; BMI: 29.8 ± 0.82) by radioimmunoassay and compared with the reference values of healthy subjects. BNP was also measured. Both plasma CNP and BNP levels were significantly lower in the obese adolescents compared to the appropriate reference values (CNP: 3.4 ± 0.2 vs 13.6 ± 2.3 pg/ml, p<0.0001; BNP: 18.8 ± 2.6 vs 36.9 ± 5.5 pg/ml, p=0.003). There was no significant difference between CNP values in males and females. As reported in adults, we observed lower plasma CNP and BNP levels in obese children, suggesting a defective natriuretic peptide system in these patients. An altered regulation of production, clearance and function of natriuretic peptides, already operating in obese adolescents, may possibly contribute to the future development of CD. Thus, the availability of drugs promoting the action of natriuretic peptides may represent an attractive therapeutic option to prevent CD.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Female; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Obesity; Radioimmunoassay; Reference Values

Hypertension is commonly associated with diabetes mellitus. The aim of the present study was to explore the pathophysiological significance of the natriuretic peptide (NP) system in hypertension associated with genetically obese/hyperglycemic Wistar fatty rats. The messenger RNA (mRNA) levels of the two biologically active NP receptors, NP-A receptor [more specific for atrial natriuretic peptide (ANP)] and NP-B receptor [more specific for C-type natriuretic peptide (CNP)], and CNP mRNA levels were determined in the aorta and kidney by ribonuclease protection assay. Plasma ANP levels were determined by RIA. Both NP-A and NP-B receptor mRNA levels in the aortae of Wistar fatty rats were double those in Wistar lean rats. Plasma ANP levels and CNP mRNA levels in the aorta of Wistar fatty rats were also significantly higher than those in Wistar lean rats. In contrast, there was no significant difference in renal levels of the mRNA for both NP receptors and CNP between the two strains. Administration of a NP-A and -B receptor antagonist, HS-142-1, to Wistar fatty rats resulted in a significant increase in systolic blood pressure and a larger decrease in plasma cGMP level than that in Wistar lean rats, with no difference in the extents of decrease in urine volume and urinary sodium excretion between the two strains. These results suggest that both the ANP/NP-A system and the CNP/NP-B system in vessels are up-regulated at the level of gene expression and may, thus, play an important role in counteracting the hypertension associated with diabetes mellitus.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Vessels; Cyclic GMP; Diuresis; Guanylate Cyclase; Hyperglycemia; Hypertension; Kidney; Male; Natriuresis; Natriuretic Peptide, C-Type; Obesity; Polysaccharides; Proteins; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger