Limits...
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.

Show MeSH

Related in: MedlinePlus

Metabolic characteristics of the NEPKO mouse under normal chow and high fat feeding regimesPlasma glucose levels in response to intraperitoneal glucose administration (a, b) measured over 2 hours after 4 weeks (a) and 15 weeks (b) of feeding and in response to insulin administration (c,d) after 7 (c) and 20 (d) weeks of feeding; closed lines: NCF mice, dashed lines: HFF mice, open symbols: NEPKO, closed symbols WT littermates. There was no difference in response between NEPKO and WT. There was no change in e) body and fat pad weight after 20 weeks of feeding and f) weight of epididymal fat pads (expressed as % of total body weight); closed bars, wild type NCF, open bars, NEPKO NCF, horizontally striped bars WT HFF, vertically striped bars NEPKO HFF. In all parameters, HFF mice differed significantly from NCF mice (*p <0.05).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3040694&req=5

Figure 5: Metabolic characteristics of the NEPKO mouse under normal chow and high fat feeding regimesPlasma glucose levels in response to intraperitoneal glucose administration (a, b) measured over 2 hours after 4 weeks (a) and 15 weeks (b) of feeding and in response to insulin administration (c,d) after 7 (c) and 20 (d) weeks of feeding; closed lines: NCF mice, dashed lines: HFF mice, open symbols: NEPKO, closed symbols WT littermates. There was no difference in response between NEPKO and WT. There was no change in e) body and fat pad weight after 20 weeks of feeding and f) weight of epididymal fat pads (expressed as % of total body weight); closed bars, wild type NCF, open bars, NEPKO NCF, horizontally striped bars WT HFF, vertically striped bars NEPKO HFF. In all parameters, HFF mice differed significantly from NCF mice (*p <0.05).

Mentions: We investigated the effect of NEP deficiency on glucose and insulin tolerance and total and epididymal fat pad weight and found no difference between NEPKO and wild type littermates on either diet (figure 5). Both NEPKO and WT HFF mice differed significantly to NCF mice in all parameters (p < 0.05) (Figure 5).


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)

Metabolic characteristics of the NEPKO mouse under normal chow and high fat feeding regimesPlasma glucose levels in response to intraperitoneal glucose administration (a, b) measured over 2 hours after 4 weeks (a) and 15 weeks (b) of feeding and in response to insulin administration (c,d) after 7 (c) and 20 (d) weeks of feeding; closed lines: NCF mice, dashed lines: HFF mice, open symbols: NEPKO, closed symbols WT littermates. There was no difference in response between NEPKO and WT. There was no change in e) body and fat pad weight after 20 weeks of feeding and f) weight of epididymal fat pads (expressed as % of total body weight); closed bars, wild type NCF, open bars, NEPKO NCF, horizontally striped bars WT HFF, vertically striped bars NEPKO HFF. In all parameters, HFF mice differed significantly from NCF mice (*p <0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040694&req=5

Figure 5: Metabolic characteristics of the NEPKO mouse under normal chow and high fat feeding regimesPlasma glucose levels in response to intraperitoneal glucose administration (a, b) measured over 2 hours after 4 weeks (a) and 15 weeks (b) of feeding and in response to insulin administration (c,d) after 7 (c) and 20 (d) weeks of feeding; closed lines: NCF mice, dashed lines: HFF mice, open symbols: NEPKO, closed symbols WT littermates. There was no difference in response between NEPKO and WT. There was no change in e) body and fat pad weight after 20 weeks of feeding and f) weight of epididymal fat pads (expressed as % of total body weight); closed bars, wild type NCF, open bars, NEPKO NCF, horizontally striped bars WT HFF, vertically striped bars NEPKO HFF. In all parameters, HFF mice differed significantly from NCF mice (*p <0.05).
Mentions: We investigated the effect of NEP deficiency on glucose and insulin tolerance and total and epididymal fat pad weight and found no difference between NEPKO and wild type littermates on either diet (figure 5). Both NEPKO and WT HFF mice differed significantly to NCF mice in all parameters (p < 0.05) (Figure 5).

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