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Neprilysin, obesity and the metabolic syndrome.

Standeven KF, Hess K, Carter AM, Rice GI, Cordell PA, Balmforth AJ, Lu B, Scott DJ, Turner AJ, Hooper NM, Grant PJ - Int J Obes (Lond) (2010)

Bottom Line: In a murine model of diet-induced insulin resistance, plasma NEP levels were significantly higher in high-fat diet (HFD)-fed compared with normal chow diet (NCD)-fed animals (1642 ± 529 and 820 ± 487 pg μl(-1), respectively; P<0.01).Tissue NEP was increased in mesenteric fat in HFD compared with NCD-fed mice (P<0.05).NEP knockout mice did not display any changes in insulin resistance, glucose tolerance, or body and epididymal fat pad weight compared with wild-type mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

ABSTRACT

Objective: Neprilysin (NEP), a zinc metalloendopeptidase, has a role in blood pressure control and lipid metabolism. The present study tested the hypothesis that NEP is associated with insulin resistance and features of the metabolic syndrome (MetS) in a study of 318 healthy human subjects and in murine obesity, and investigated NEP production by adipocytes in-vitro.

Methods and results: In 318 white European males, plasma NEP was elevated in the MetS and increased progressively with increasing MetS components. Plasma NEP activity correlated with insulin, homoeostasis model assessment and body mass index (BMI) in all subjects (P<0.01). Quantitative reverse transcriptase PCR (RT-PCR) and western blotting showed that in human pre-adipocytes NEP expression is upregulated 25- to 30-fold during differentiation into adipocytes. Microarray analysis of mRNA from differentiated human adipocytes confirmed high-NEP expression comparable with adiponectin and plasminogen activator inhibitor-1. In a murine model of diet-induced insulin resistance, plasma NEP levels were significantly higher in high-fat diet (HFD)-fed compared with normal chow diet (NCD)-fed animals (1642 ± 529 and 820 ± 487 pg μl(-1), respectively; P<0.01). Tissue NEP was increased in mesenteric fat in HFD compared with NCD-fed mice (P<0.05). NEP knockout mice did not display any changes in insulin resistance, glucose tolerance, or body and epididymal fat pad weight compared with wild-type mice.

Conclusion: In humans, NEP activity correlated with BMI and measures of insulin resistance with increasing levels in subjects with multiple cardiovascular risk factors. NEP protein production in human adipocytes increased during cell differentiation and plasma and adipose tissue levels of NEP were increased in obese insulin-resistant mice. Our results indicate that NEP associates with cardiometabolic risk in the presence of insulin resistance and increases with obesity.

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Relationship between plasma NEP, insulin resistance and BMI in healthy humansA: Plasma NEP is increased in overweight and obese subjects. Data presented as median and 75th percentile; * p<0.0001 comparing overweight (BMI 25-30) and obese subjects (BMI >30) with those with BMI <25 (after adjusting for multiple comparisons). B: Circulating NEP increases across increasing quartiles of HOMA. Data presented as median and 75th percentile; * p<0.0001 comparing quartiles 3 and 4 with quartile 1 and for comparing quartile 2 with 4, and § p=0.006 comparing quartiles 3 with 4 (all after adjusting for multiple comparisons).
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Figure 1: Relationship between plasma NEP, insulin resistance and BMI in healthy humansA: Plasma NEP is increased in overweight and obese subjects. Data presented as median and 75th percentile; * p<0.0001 comparing overweight (BMI 25-30) and obese subjects (BMI >30) with those with BMI <25 (after adjusting for multiple comparisons). B: Circulating NEP increases across increasing quartiles of HOMA. Data presented as median and 75th percentile; * p<0.0001 comparing quartiles 3 and 4 with quartile 1 and for comparing quartile 2 with 4, and § p=0.006 comparing quartiles 3 with 4 (all after adjusting for multiple comparisons).

Mentions: The clinical and biochemical characteristics of the 318 subjects according to the presence of the metabolic syndrome are presented in Table 1. Seventy nine subjects (24.8%) fulfilled the IDF criteria for exhibiting the MetS, 229 subjects (75.2%) did not have the MetS by these criteria. Subjects with the MetSIDF were slightly older with significantly higher BMI, cholesterol, LDL, insulin and HOMA than those without the MetSIDF. The haemostatic factors PAI-1 and tPA were also significantly higher in subjects with the MetSIDF. The prevalence of smoking and family history of cardiovascular disease was similar in the two groups. Plasma NEP concentration was significantly associated with BMI (p for trend <0.0001) increasing from a median (25th and 75th percentiles) of 0.155 (0.048, 0.310) nmol/L in those with BMI <25 kg/m2 to 0.358 (0.233, 0.719) nmol/L (p<0.001) in those with BMI>30 kg/m2 (Fig 1A). Similarly, there was a stepwise increase in NEP concentration with increasing quartiles of HOMA (Fig 1B), however, only the difference in NEP between quartiles 4 and 1 were significant after adjustment of age, sex and BMI (adjusted NEP levels: 0.199 [0.150, 0.265] nmol/L in HOMA quartile 1 vs. 0.366 [0.275, 0.488] nmol/L in HOMA quartile 4, p=0.015 after adjustment for multiple comparisons). NEP activity was significantly higher in subjects with the MetSIDF compared to those without (0.38 vs 0.2 nmol/L, respectively, p<0.001), and increased progressively with the number of MetSIDF components, being ~8-fold higher in those with 5 MetSIDF components compared with those with no MetSIDF (p<0.0001 after Bonferroni adjustment for multiple comparisons, Figure 2A). NEP was also significantly higher in subjects with a family history of cardiovascular disease (0.18 vs 0.30 nmol/L, respectively, p<0.001). Plasma NEP correlated with fasting insulin (r=0.3, p<0.001), HOMA (r=0.3, p<0.001), BMI (r=0.34, p<0.001), tPA (r=0.44, p<0.001) and PAI-1 (r=0.41, p<0.001) in all subjects. In a linear regression analysis (excluding subjects with NEP below the assay threshold), significant predictors of plasma NEP concentration were triglyceride, tPA, DBP and PAI-1, which together explained 25% of variance in NEP. ROC curve analysis was used to determine a cut-point for NEP in relation to MetSIDF (see figure 2B, inset); on the basis of this analysis NEP was dichotomised according to NEP <0.2028 nmol/L or ≥0.2028 nmol/L for further analysis. Logistic regression analysis, with backwards stepwise selection for cardiovascular risk factors not directly contributing to the MetS definition, including NEP cut-point, age, smoking, HOMA, LDL, PAI-1 and tPA, was carried out. This analysis indicated that NEP was independently associated with MetSIDF (OR for NEP ≥0.2028 nmol/L, 2.31 [1.14, 4.66], p=0.02) and each of the MetS subcomponents (Figure 2B).


Neprilysin, obesity and the metabolic syndrome.

Standeven KF, Hess K, Carter AM, Rice GI, Cordell PA, Balmforth AJ, Lu B, Scott DJ, Turner AJ, Hooper NM, Grant PJ - Int J Obes (Lond) (2010)

Relationship between plasma NEP, insulin resistance and BMI in healthy humansA: Plasma NEP is increased in overweight and obese subjects. Data presented as median and 75th percentile; * p<0.0001 comparing overweight (BMI 25-30) and obese subjects (BMI >30) with those with BMI <25 (after adjusting for multiple comparisons). B: Circulating NEP increases across increasing quartiles of HOMA. Data presented as median and 75th percentile; * p<0.0001 comparing quartiles 3 and 4 with quartile 1 and for comparing quartile 2 with 4, and § p=0.006 comparing quartiles 3 with 4 (all after adjusting for multiple comparisons).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040694&req=5

Figure 1: Relationship between plasma NEP, insulin resistance and BMI in healthy humansA: Plasma NEP is increased in overweight and obese subjects. Data presented as median and 75th percentile; * p<0.0001 comparing overweight (BMI 25-30) and obese subjects (BMI >30) with those with BMI <25 (after adjusting for multiple comparisons). B: Circulating NEP increases across increasing quartiles of HOMA. Data presented as median and 75th percentile; * p<0.0001 comparing quartiles 3 and 4 with quartile 1 and for comparing quartile 2 with 4, and § p=0.006 comparing quartiles 3 with 4 (all after adjusting for multiple comparisons).
Mentions: The clinical and biochemical characteristics of the 318 subjects according to the presence of the metabolic syndrome are presented in Table 1. Seventy nine subjects (24.8%) fulfilled the IDF criteria for exhibiting the MetS, 229 subjects (75.2%) did not have the MetS by these criteria. Subjects with the MetSIDF were slightly older with significantly higher BMI, cholesterol, LDL, insulin and HOMA than those without the MetSIDF. The haemostatic factors PAI-1 and tPA were also significantly higher in subjects with the MetSIDF. The prevalence of smoking and family history of cardiovascular disease was similar in the two groups. Plasma NEP concentration was significantly associated with BMI (p for trend <0.0001) increasing from a median (25th and 75th percentiles) of 0.155 (0.048, 0.310) nmol/L in those with BMI <25 kg/m2 to 0.358 (0.233, 0.719) nmol/L (p<0.001) in those with BMI>30 kg/m2 (Fig 1A). Similarly, there was a stepwise increase in NEP concentration with increasing quartiles of HOMA (Fig 1B), however, only the difference in NEP between quartiles 4 and 1 were significant after adjustment of age, sex and BMI (adjusted NEP levels: 0.199 [0.150, 0.265] nmol/L in HOMA quartile 1 vs. 0.366 [0.275, 0.488] nmol/L in HOMA quartile 4, p=0.015 after adjustment for multiple comparisons). NEP activity was significantly higher in subjects with the MetSIDF compared to those without (0.38 vs 0.2 nmol/L, respectively, p<0.001), and increased progressively with the number of MetSIDF components, being ~8-fold higher in those with 5 MetSIDF components compared with those with no MetSIDF (p<0.0001 after Bonferroni adjustment for multiple comparisons, Figure 2A). NEP was also significantly higher in subjects with a family history of cardiovascular disease (0.18 vs 0.30 nmol/L, respectively, p<0.001). Plasma NEP correlated with fasting insulin (r=0.3, p<0.001), HOMA (r=0.3, p<0.001), BMI (r=0.34, p<0.001), tPA (r=0.44, p<0.001) and PAI-1 (r=0.41, p<0.001) in all subjects. In a linear regression analysis (excluding subjects with NEP below the assay threshold), significant predictors of plasma NEP concentration were triglyceride, tPA, DBP and PAI-1, which together explained 25% of variance in NEP. ROC curve analysis was used to determine a cut-point for NEP in relation to MetSIDF (see figure 2B, inset); on the basis of this analysis NEP was dichotomised according to NEP <0.2028 nmol/L or ≥0.2028 nmol/L for further analysis. Logistic regression analysis, with backwards stepwise selection for cardiovascular risk factors not directly contributing to the MetS definition, including NEP cut-point, age, smoking, HOMA, LDL, PAI-1 and tPA, was carried out. This analysis indicated that NEP was independently associated with MetSIDF (OR for NEP ≥0.2028 nmol/L, 2.31 [1.14, 4.66], p=0.02) and each of the MetS subcomponents (Figure 2B).

Bottom Line: In a murine model of diet-induced insulin resistance, plasma NEP levels were significantly higher in high-fat diet (HFD)-fed compared with normal chow diet (NCD)-fed animals (1642 ± 529 and 820 ± 487 pg μl(-1), respectively; P<0.01).Tissue NEP was increased in mesenteric fat in HFD compared with NCD-fed mice (P<0.05).NEP knockout mice did not display any changes in insulin resistance, glucose tolerance, or body and epididymal fat pad weight compared with wild-type mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

ABSTRACT

Objective: Neprilysin (NEP), a zinc metalloendopeptidase, has a role in blood pressure control and lipid metabolism. The present study tested the hypothesis that NEP is associated with insulin resistance and features of the metabolic syndrome (MetS) in a study of 318 healthy human subjects and in murine obesity, and investigated NEP production by adipocytes in-vitro.

Methods and results: In 318 white European males, plasma NEP was elevated in the MetS and increased progressively with increasing MetS components. Plasma NEP activity correlated with insulin, homoeostasis model assessment and body mass index (BMI) in all subjects (P<0.01). Quantitative reverse transcriptase PCR (RT-PCR) and western blotting showed that in human pre-adipocytes NEP expression is upregulated 25- to 30-fold during differentiation into adipocytes. Microarray analysis of mRNA from differentiated human adipocytes confirmed high-NEP expression comparable with adiponectin and plasminogen activator inhibitor-1. In a murine model of diet-induced insulin resistance, plasma NEP levels were significantly higher in high-fat diet (HFD)-fed compared with normal chow diet (NCD)-fed animals (1642 ± 529 and 820 ± 487 pg μl(-1), respectively; P<0.01). Tissue NEP was increased in mesenteric fat in HFD compared with NCD-fed mice (P<0.05). NEP knockout mice did not display any changes in insulin resistance, glucose tolerance, or body and epididymal fat pad weight compared with wild-type mice.

Conclusion: In humans, NEP activity correlated with BMI and measures of insulin resistance with increasing levels in subjects with multiple cardiovascular risk factors. NEP protein production in human adipocytes increased during cell differentiation and plasma and adipose tissue levels of NEP were increased in obese insulin-resistant mice. Our results indicate that NEP associates with cardiometabolic risk in the presence of insulin resistance and increases with obesity.

Show MeSH
Related in: MedlinePlus