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Neprilysin, obesity and the metabolic syndrome

International Journal of Obesity volume 35, pages 1031–1040 (2011)Cite this article

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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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Acknowledgements

This study was partially funded by British Heart Foundation grant no. PG/02/106/14434. Katharina Hess is supported by a grant from the German ADUMED foundation.

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Author notes

  1. K F Standeven and K Hess: Joint first authors.

Authors and Affiliations

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

    K F Standeven, K Hess, A M Carter, G I Rice, P A Cordell, A J Balmforth, D J Scott & P J Grant

  2. Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK

    G I Rice, A J Turner & N M Hooper

  3. Children's Hospital, Harvard Medical School, Boston, MA, USA

    B Lu

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  1. K F Standeven
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Correspondence to P J Grant.

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Standeven, K., Hess, K., Carter, A. et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes 35, 1031–1040 (2011). https://doi.org/10.1038/ijo.2010.227

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